9.4: Chromosome & Chromosomal Aberrations in Man

Chromosomes & Basics

are complex str. located in the cell nucleus visible only in dividing cells.
interphase nucleus has a loose & indistinct network of nucleoprotein fibres called chromatin
To get the cell with their chromosomes in this condensed state they are exposed to a mitotic inhibitor which blocks formation of the spindle & arrests cell division at metaphase stage.
Some ex. of tissues used to obtain chromosome peripheral blood, bone marrow, amniotic fluid, and products of conception.
Study of chromosomes is Karyology

Chromosomal Structure

Composed of DNA, histone and non-histone proteins, RNA & polysaccarides. They are basically the ” packages” that contain the DNA.
Under microscope they appear as thin, thread like str.
Every chromosome essentially has a primary constriction or the centromere on the side of which disc shaped str. called kinetochores are present.
Centromere holds the two chromatids of a chromosome.

Types of Chromosomes – Based on the position of the centromere, chromosome can be classified into four types

Metacentric Chromosome – middle centromere forming two equal arms of the chromosome.
Sub-metacentric Chromosome – centromere slightly away from the middle resulting one shorter & one longer arm
Afrocentric Chromosome – centromere situated close to its end forming one extremely short & one very long arm.
- Acrocentrics frequently have a secondary constrictions connecting small pieces of DNA called stalks & satellites
Telocentric Chromosome – These have terminal centromere.

Sometimes a few chromosomes have non-staining 2° constriction at a constant location. They gives the appearance of a small fragment c/a Satellite.

Ideogram

is basically a “chromosome map” showing the r/l between the short and long arms, centromere (cen), and in the case of acrocentric chromosomes the stalks (st) and satellites (sa).
The specific banding patterns are also illustrated.
Each band is numbered to aid in describing rearrangements.

Features

Normal human somatic cells have 46 chromosomes: diploid
- 22 pairs, or homologs, of autosomes (chromosomes 1‐22) and
- two sex chromosomes
  - Females carry two X chromosomes (44,XX) while
  - males have an X and a Y (44,XY).
Germ cells (egg and sperm) have 23 chromosomes:
- one copy of each autosome plus a single sex chromosome –
- This is referred to as the haploid number.
One chromosome from each autosomal pair plus one sex chromosome is inherited from each parent
Mothers can contribute only an X chromosome to their children while fathers can contribute either an X or a Y.
Chromosome 1 is the designation for the largest human chromosome.

Chromosomal Aberrations

Introduction – Any deviation from the normal karyotype is known as a chromosome aberrations/abnormality. Some chromosome abnormalities are harmless, some are associated with clinical disorders. Half of all spontaneous abortions are due to chromosome abnormalities

These aberrations may be of two kinds –

Spontaneous Aberration – These are the naturally occurring structural rearrangements of the chromosomes. The reason behind such aberrations is not clearly understood. Factors like cosmic radiation, nutritional insufficiencies & several other environmental factors may hamper the original chromosomal structure or number.
Induced Aberration – these are the architectural changes deliberately produced by the use of physical or chemical agents. A variety of agents are able to induce mutations. They also cause breakage in chromosomes & all these result in chromosomal aberrations.

All structural & numerical aberrations in chromosomes are due to the action of Mutagens of various types :

Physical Mutagens – B-rays, X-rays, Cosmic rays, U.V rays, extreme temp (Cold & Hot)
Chemical Mutagens – Base analogous, alkylating agents, mustard gas, acridine dyes
Biological Mutagens – Viruses ; Herpes, Rubella

Geneticist are more concerned with the spontaneous aberrations b/c these phenomena occur naturally, without any known casual factor. They have grouped these aberrations into two

Structural Aberration
Numerical Aberration

Both numerical & Structural aberrations can also be classified into

Constitutional – Those are born with – Familial
Acquired – Those that arise as 2ndry changes due to other disease like cancer – De Novo

Numerical Chromosomal Aberrations / Heteroploidy

Introduction – are genetic disorders usually caused by a failure of chromosome division & involve the variation in number of chromosomes (autosomal & sex), which result in deviation from the diploid state ; which is often referred as heteroploidy. Individuals having the variant chromosome number are known as heteroploids

Normal chromosomal no. are haploid in gametes & diploid in zygotes – Euploidy (true no.) Based on deviation from this Heteroploids can be divided into two classes

Aneuploidy – is the condition when an organism gains or losses one or more chromosomes & not the entire set. These phenomena arises due to non-disjunction or abnormal distribution of chromosomes during Anaphase of meiosis.
- Loss of one chromosome is monosomic (2n-1)
  - Sex chromosome Monosomy
    - Turner Syndrome – due to monosomy of X chromosome
- Gain of one chromosome is trisomic(2n+1)
  - Sex Chromosome Trisomy
    - Klinefelter Syndrome – (XXY)
    - Super female
  - Autosomal Trisomy
    - Downs Syndrome (21st Trisomy)
    - Edward Syndrome (18th Trisomy)
    - Patan Syndrome (13th Trisomy)
Euploidy – is the condition when an organism, gains or losses one or more complete set of chromosomes, thus causing change in ploidy number. For ex triploidy(3n), tetrapliod(4n etc) .
- Diploid (2n) is considered to be normal
- Euploidy can be further divided into
  1. Monoploids– denotes the presence of a single copy of single genome (x) as like haploids, representing the gametic chromosome number of species (n)
  2. Polyploids – denotes the presence of more than two genomes in a cell is known as polyploids. This means, org possess more than two sets of chromosomes in their nuclei.

A few numerical abnormalities support development to term, either b/c the chromosome is small &/ or contains relatively few genes or b/c there is a natural mechanism present to help adjust gene dosage.

Symbols ranges from intellectual to physical disability, often resulting in developmental & health issues. Although there is no cure, many symptoms can be treated with supportive therapy to minimise the impact of numerical aberrations.

Polyploidy of Autosome are more harmfulTrisomy Autosomes carry a no. of genes that are expressed in cell, hence abnormal condition related to autosomes are likely to produce more harmful & deleterious conditions.Trisomy of 21 is tolerated more but those of 18 & 13 are more harmful & result in death of its possessor soon after birth.As chromosome 21 is much smaller & so contain lesser no. of genes expressed in cell. So there is imbalance of lesser no. of gene products hence it is tolerated for longer period.
Monosomy of Autosome is Even less ToleratedAs it is most likely to result in absence of a no. of gene product without which survival is never distinct possibility. So fetuses’ are aborted during embryonic development
Why is monosomy of X tolerated & not monosomy of autosome ?One of two X chromosome in female remains inactivated(c/a Barr Body , however small portion of it is essential for normal development of females since that portion is absent so abnormalities develops) so, there only one functional chromosomes.Even in the case of monosomy there is only one functional chromosome so not any issue.
Disomy of Y interferes in the growth & development only in Limited wayAs Y chromosome contains only limited no. of genes expressed in cell. Majority of its DNA is non functional & made up of respective sequences.

Non Disjunction

occur either in the 1st or 2nd meiotic divisions
Occasionally, a homologous chromosomes , reasons not fully understood, will fail to seprarate during meiosis.
results in a egg or sperm with one more or one less than the noramal complement of chromosomes (trisomy or monosomy),
mostly the formed gamete doesn’t survive but in some cases, some gametes do survive, producing individuals with abormal chromosome no.
So, these have serious genetic consequences, can affect either the sex chromosome or autosomes.
Non Disjunction & Increasing Maternal age ; as with increasing the maternal age the spindle fibers, separating the chromosomes at the time of cell division are weakening. As spindle fibers can’t be of same strength through out the life as they all the ova form before birth.
Mosaicism – indicates a situation in which different cells in the same individual have different numbers of chromosomes.
- Mosaicism occurs due to non-disjunction during mitosis.
- It includes mosaic trisomy, mosaic monosomy & mosaic triploidy
- Mosaic trisomy occurs when the extra chromosome is present in a some (but not all) of the cells of the body.

Autosomal Chromosomal Abnormalities

Sex Chromosomal Abnormalities

Turner’s Syndrome	Klinefelter Syndrome	Triple X Syndrome / Superfemales	XYY / Criminal S/ Jacob S / Superman Syndrome

• Monosomy XO (45,X) – in ♀ due to non disjunction.• One out of 2500 female births• Ullrich – Turner Syndrome / Gonadal Dydgenesis	• ↑ in no. of X chr-me in male with genetic composition 44 + XXY ; 44+XXXY ; 44+XXXXY• 47, XXY (normally ref) • due to chr-me non disjunction during meiosis • Per 700 live births• Older mother have increased risk	• 47, XXX / Super Females due to chromosomal non disjunction• per 950 female live birth	• 47, XYY• Originally c/l criminal syndrome – now known more as Jacob Syndrome• 97% of men don’t know their karyotype as the phenotype is “normal”• Usually detected only during a genetic analysis• This mutation is only present in some cells• XYY Nondisjunction
Symptoms
Prenatal or before birth• excess fluid collection on the back of neck or other parts of the body• Many internal abnormalities in cardiovascular & renal systemAt birth or during infancy• Wide or web-like neck• Small lower jaw• High, narrow roof of the mouth• Low hairline at the back of the head• Ears set a little lower than normal• Broad chest with widely spaced nipples• Arms turning outward at the elbows• Short fingers and toes• Narrow fingernails & toenails that are turned upward• Swelling of the hands & feet, especially at birth• Reduced height at birth• Delayed growthSymptoms noted in older girls, teens & young women• Short height• Limited 2° sexual chr• Delayed or no puberty• Amenorrhoea• Osteoporosis• Incomplete sexual dev• Sterility	• Abnormal body proportions (long legs, short trunk, shoulder equal to hip size)• Tall height• Abnormally large breasts (gynecomastia)• Normal dev of external genital but testes are very small & do not produce sperms hence the patient is sterile. Testes are infantile.• Infertility• Poor growth of facial & bodily hair• Diminished libido & potency• Voice is high pitched	• Weak muscle tone (hypotonia), and behavioral and emotional difficulties• Seizures or kidney abnormalities occur in about 10 percent of affected females.• Physically normal & able to bear children• Menstrual irregularities & early onset of menopause.	• Tall Statures• large teeth• Weakness• Prominent glabella• Asymmetrical face• Long Ears• Sunken Chest• Sever Adolescent Nodulocystic acne
Intelligence
• Quite normal , retardation is uncommon• Mild forms of mental impairment are revealed by detailed intelligence testing.• Learning disabilities• Problem -understanding social situations	• avg. intelligence. But speech & lang learning is affected. But mental disability ↑ with ↑ in no. of X chr-me (chr-some) • Able to get higher education with special efforts on speech & language learning.	• Increased risk of learning disabilities and delayed development of speech and language skills.• Delayed development of motor skills (such as sitting and walking),	• 50% of boys show risks of learning disabilities, language acquisition and delayed speech• Behavioral problems• Poor fine motor coordination
Health & Life Expectancy
• Lymphedema of feet at birth• May have congenital heart malformation & suffer great risk of heart elements• Suffer from primary amenorrhea in adults• Therapy with estrogen allow the adult to develop 2° sexual character & live a comparatively satisfactory, although sterile married life.	• Androgen deficiency +nt• 2°sexual characters are poorly developed• Growth & physical deve quite normal• Males tend to be taller for their age• Vascular disorders & Ischemic Heart Disease

Fragile X syndrome

46 XY in male : 46 XX in female. There is satellite on long arm of X chromosome.
Both males & females may be sufferer but mostly male suffer because they have oly one X chromosome
Symtoms
- Large head & ears, prominent chin & larger testes in males
- It produces mental retardation

Structural Chromosomal Aberrations

Introduction – are genetic disorders caused due to alteration/change in structure of one or more chromosome without any change in the chromosome number.

Mechanism – it involves a rearrangement through loss, gain or reallocation of chromosomal segments.

These can be divide further based on type of abnormalities

Balanced Structural Abnormalities – these involve the rearrangement of genetic material but with no overall gain or loss. eg Gene Transfer (Inversions & Translocations or Transposition)
- During gene transfer, two things can happen
  - Genes from one chromosome get transferred to another chromosome
  - Genes can get rearranged on the same chromosome
- these can have immediate effect
- But major consequence is the production of eggs or sperm with incomplete or partially duplicated sets of chromosomes
- Normally recombination b/w homologous chromosomes during meiosis, changes specific alleles on a given chromosome & adds to variation in a population.
Unbalanced str. abnormalities – these involve genetic material being gained or lost.
- Even tiny unbalance str. abnormalities can affect many genes & have severe effects on the individual

Deletion – The loss of chromosome segment, (a fragment without centromere) is known as deletion. The deletion of a portion of chromosome is very rare event.

The effects are typically severe & lethal since critical genes will be missing including striking genetic & morphological / physiological consequences.
Type of deletion
- Terminal Deletion – Ex 5P – Cri -du-chat syndrome
- Interstitial Deletion
- Micro Deletion – (Ex Angleman syndrome, Prader willi syndrome)
Each deletion gives rise to distinct set of symptoms which characterises an abnormality & called as syndrome.
Few syndrome & abnormalities
- Wolf Hirschhorn syndrome – Deletion from tip of short arm of chromosome 4
- Cri Du Chat Syndrome – Deletion aberration on Chromosome 5 on p-arm { Karyotype (46, XX) 5p }
- WAGR Syndrome – Micro-deletion from short arm of chromosome 11
- Prader – Willi / Angelman – Micro-deletion from short arm of chromosome 15 → power growth & development
- DiGeorge – Micro- deletion from long arm of chromosome 22
- Philadelphia 22 – specific deletion in chromosomes 22 → associated with chronic Myelogenous leukemia

Duplication – in this process – a mutation causing part of the chromosome to be repeated, resulting in extra genetic material. I.e presence of additional chromosome segment in nucleus.

A deleted chromosome fragment can attach to its homologue, thereby duplicating a region of genes
Types
- Tandem Duplication – when the extra – chromosomal segment is located immediately after the normal segment following the same orientation. I.e same genetic sequence is maintained
- Reveres Duplication – When the extra -chromosomal segment is located immediately after the normal segment but following the opposite orientation.
- Displaced Duplication – The additional segment is found to be located in the same chromosome but away from the normal segment.
- Translocation Duplication – When the additional chromosome segment is found to be translocated into a non-homologous chromosome.
In some cases, a segment of a gene or chromosome undergoes multiple repetitions
In general, duplication don’t produce any drastic consequences as like deletion in terms of phenotype & survival.

Inversions – when a segment of a chromosome is found to be oriented in reverse direction, it is called inversion.

For an inversion, a group of genes can have their order reversed in the chromosome so that a gene sequence that should be A-B-C-D-E-F-G-H is changed to A-B-F-E-D-CG-H instead
This result in part of the DNA being backwards & unreadable
Many gametes are not viable after inversions
Types
- Paracentric Inversion – when the inverted segment doesn’t contain a centromere
- Pericentirc Inversion – when the inverted segment contains a centromere

Translocations – It involves transfer one portion of a chromosome to a different part of the chromosome (intrachromosomal) or to a different chromosome altogether (interchromosomal).

There are two key types:
- Reciprocal or Balanced: Translocation involve exchange of genes b/w non homologous chromosomes
- Robertsonian: an entire chromosome attaches to another.
  - Aka called Centric fusion
  - Human 2nd chromosomes pair : is the product of this ; as in apes there are 13 & 12 acrocentric chromosomes ; and in cases of human there are 11 & 10 respectively in males and females.

Ring chromosomes – is an aberrant Chromosome whose ends have fused together to form a ring.

Formed when – a portion of a chromosome has broken off and formed a circle or ring
Genetic material may or may not get lost

Isochromosome – formed by deletion of one arm & duplication of the other, whereby the duplicate attaches itself in an inverted manner. Thus, the arms appear like mirror images of each other

Structural aberrations also include some disorders characterised by chromosomal instability & breakage.

Extra Nuclear Inheritance

Mitochondria are self replication & have small circular pieces of DNA & that DNA is transcribed & translated within the organelle.
In sexual reproduction, only the egg cell’s cytoplasm is passed to the zygote, so only material mitochondrial DNA will be transmitted from generation to generation.
Some genetic disorders are traced to mutations in mitochondrial DNA that codes for proteins
Mutations in mitochondrial DNA may be one reason cells age.

Sex Determination

Human male & female differs in X & Y chromosome
Y chromosome contains the important male determinants b/c testicular differentiation doesn’t occur in its absence. In it 2.1 kb gene, c/a SRY gene (Sex determining Region Y) it synthesize a protein c/a SRY protein .
- which act on promotor of the gene for mullerian inhibiting substance that cause regression of female reproductive system & development of testes in female reproductive system & development of testes in the male embryo.
- A curious feature of SRY gene is that it has no introns. It is probable that the gene has been inserted in human genome later in evolution through the action of reverse transcriptase, a viral polymerase enzyme. if this is correct, sexuality in human may become a fall out of viral activity.
If father contributes a Y,
- the undifferentiated embryonic gonad will began to differentiate into a testis at about 1.5 to 2 months.
- At the end of the 3rd month, the foetal testis elaborate androgenic hormones which masculinize the external genitalia.
If father contributes a X,
- the embryonic gonad will remain undifferentiated until about the 4 months when it becomes distinguishable as an ovary.
- The fetal ovary doesn’t produce hormones which influence the internal genital ducts or external genitalia.
2nd Imp. stage in sexual differentiation, the development of the internal & external genitalia is therefore dependent entirely on the presence of absence of a competent fetal testis
In certain region, SRY region of Y chromosome can be broken & translocated to X chromosomes.
- If one of the two x chromosomes contain a translocatd SRY gene then XX would develop into males.
- if SRY region break off & deleted from Y chromosome, person with XY chromome would not develop into males.

Mosaicism

Introduction – Mosaics involves the presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilised egg.

Mosaics arise by non-disjuntion of chromomes usually X & Y during embryogenesis. Anaphase Lag & endoreplication are other cause of Mosaicism
It includes mosaic trisomy, mosaic monosomy & mosaic triploidy
Mosaic trisomy occurs when the extra chromosome is present in a some (but not all) of the cells of the body.
Mosaics are usually found in abnormal numbers & structural mosaics are very rare.
Hence, any routine cytogenetic analysis should involve 15-20 cells to rule out clinically significant mosaicism.

Intersex

Introduction – An intersex is a sterile individual having the characteristic intermediate b/w that of male & female. Intersex arise when there is conflict b/w the 4 criteria of sex, namely

The chromosomal Sex
The sex of the gonad
The physiological Sex
The external Apparent Sex

Causes of Origin of Mosaics

Types of Mosaics – based on Gonadal Histology

True Hermaphrodites / Gynandromorph
- Gyne -Female | Andro-Male| Morph-Form ; phenotype ranges from appearance to be almost male to appearance almost female.
- Most of true hermaphrodites have karyotype 46, XX but variable
- Gonadal tissue – Mosaics of male cells & female cells or ovary on one side & testes on the other
  - Have both ovarian & testicular tissue & mixed masculine & feminine genital structures
  - Rarely, in them, external genitalia is fully masculinized
- depending on the no. of cell of male line & female line constitutes the Gonadal primordia they will be masuline or feminine.
  - if more male cells testes will be dominant to if
  - Female cells are more then ovary will be dominant
  - It equal, ovo – testes in the result.
- They have both masculine & feminine characteristics
  - both male & female hormones are secreted in them
- This condition is inherited in an autosomal recessive manner
Mixed Gonadal dysgenesis
- Phenotype – short stature, ambiguous genitalia
- Gonad – both testicular tissue & primitive gonadal tissue called steaks
- When streaks are bilateral, then disorder, is pure gonadal dysgenesis
- Phenotypically females
- Karyotype : 46 XY/46 , XO mosaic karyotype
Pseudohermaphrodite
- are individuals who has only one type of gonadal tissue ; are partly male & partly female in genitalia & 2° sex characteristics
- Presence or absence of barr body helpds doctors to decide whether the dominant genotype is XX or XY.
- Male Pseudohermaphrodites
  - Gonads – Have gonadal tissue that is only testicular
  - Karyotype – 46, XY
  - phenotypes – External & internal genitalia are ambiguous, but this is variability
    - In some cases a female phenotype is seen in complete form – testicular feminization syndrome
    - In other cases testes are seen with presence of uterus
    - It has undesended testes, a small penis, a rudimentary vagina, no scortal scas, presence of breasts & is sterile. In some case, they have been converted to females by surgical method.
  - Etiology –
    - can happen b/c of inadequate producing of androgens – Gonandal dysgenesis in embryo Gonadotropins abnormality or Error in synthesis of testosterone.
    - inadequate response to androgens during critical growth phase – androgen target cell abnormality called as testicular feminisation or androgen insensitivity syndrome → X linked disorder
- Female Pseudohermaphrodites
  - Phenotypes – Have ovaries & normal female internal genitalia but ambiguous external geneitalia
    - Has underdeveloped ovaries, infantile uterus & vagina, rudimentary penis, little breast.
  - Gonads – Testicular tissue.
  - They are genetically normal females with karyotype 46, XX
  - Etiology
    - The ambiguous external genitalia result from exposure to excessive amounts of androgens in utero (inside uterus)
    - The offending androgen may be
      - Exogenous – progesterone given to mother prevent miscarriage
      - Endogenous – enzymatic block due to aberrations in chromosome 6 (adrenal virilism) ; congenital adrenal hyperplasia – autosomal recessive disorder → ↑ ACTH → ↑ in androgens → masculinisation in female foetus (adrenal virilism)
      - Overactive adrenal cortex of the mother.
  - Some of them have been converted to males by suitable surgery & hormone therapy in early childhood.

Chimaera

Definition – They are formed by fusion of two zygotes & all the cell populations & derived by two zygotes.

Types of Chimera

Dispermale Chimera : resulting from 2 sperms & 2 ova
Blood Chimera : e.g DZ twins of opposite sex. In such cases, female is masculinized by testosterone secreted by testes of male embryo.

Genetic / Genomic Imprinting

Introduction – Genetic imprinting is a contrary to law of equivalencegiven by Mendel. It is species specific & erasable. It has much significance

Law of Equivalence – Acc. to Mendel, irrespective of source (Male & Female) of allele, the alleles behave equally while transmitting from one generation to another.

He discovered this in reciprocal cross.
Law of Equivalence is not Universal
- Differs from gene to gene in same animal
- Differs from animal to animal
However, Genetic Imprinting is Exception to Law of Equivalence

Definitions – Genetic imprinting is the differential inheritance of genetic material from the mother versus the father. I.e the expression of small number of human genes is influenced by whether the gene has been inherited from the mother or father.

Depending upon the gene, copy from mother (or) father is epigenetically silenced.
Epigenetically means, changes in organisms caused by modification of gene expression rather than alteration of genetic code itself.

Examples

Male Sex Chromosomes – affect different phenotype compared to females
Huntington Chorea (Autosomal disease)
- Symptoms same but the time of initiation of symptoms & severity different depending upon whether gene is paternal or maternal.
Fragile X Syndrome
Embryonic tumors
Hereditary Glomus Tumor – inherited disease from father

deletion in region concerned with placental dev, it have no effect effect if inhertited maternally but may cause a faliure of placental development in inherited paternally.

Angelmann syndrome – maternally inherited
- deleted chromosome ch15 – 11-13
- Happy disposition, mental retardation, large mouth, protruding, tongue & seizures.
Prader Willi Syndrome – Always derived paternally
- Deletion in position 11, 12, 13 in Ch. 15
- Development delay, obesity & hypogonadism

Mechanism of Genetic Imprinting

During its passage from the male & female parents, the autosomal & X chromosomes are stamped differently for different parents i.e male & female parents
so that the chromosomes bear the marking of the parents from which they are originating from.
Much of the autosomes from the two parents are similar in genetic constitution but behaviorally they differ in the manner of expression.

Casuse of Genetic Imprinting : Selective Methylation of DNA

DNA methylation is a usual process to control functioning of genes & brought about by DNA methylase. It adds Methyl group to cytosine. If cytosien in one Strand is methylated, it would pass through Guanine to the other Strand.
One of the theories is, Selective Methylation of DNA (adding a methyl group to cytosine by DNA methylase) – it has been discovered that genes from mother are more methylated than the other coming from the father.
The Degree of methylation brings about qualitative & quantitative change i.e excessive methylation results in inhibiting the activity of gene & is responsible for number of disorders.
It is generally understood that imprinting affects a chromosome which survives mitosis but not meiosis.

Characteristic of Genome Imprinting

Imprinted genome expresses variously →Male & female genes have different magnitudes of expression & time of expression
Genetic Imprints are Erasable. Imprinting done in gonadal tissue – Such markings are erased during gametogenesis – offspring marks his own sex
Genetic Imprinting is not a Rule – Discovered only in some male & female genes – Majority of genes are not imprinted.
Genetic Imprinting is species Specific – A gene imprinted in one species may not be imprinted in another species.
Gene imprinting is most common in mammals & flowering plants
- different pheotypic effects during development of gameted.
- b/a both groups directly nourish their embryo (Adaptation theory)
Gene impriting is implicated in many diseases
- it has been implicated in triggering of many human genetic disease such as fragile X syndrome, Angelman Syndrome, Embryonic tumours, Cancers & several other patterns of inheritance of human disease.

Significance

It has biomedical significance as on that basis it can be identified that genes in the offspring are of paternal or maternal origin.
Significant in studying differential inheritance.
Genome imprinting helps to know the effect of deletion in different sexes.
It shows variations in diseases according to gender. E.g Myotonic Dystrophy
To know the source of allele. chances of survivabiltiy depend upon marking other, their survival capacity declines

Conclusion – The differnece b/w maternally & paternally derived genes are significant in studing the differential inheritance. A most recent discovery of new disease due to this phenomenon is Myotonic dystrophy that affects the growing fetus.

Genetic Screening

Introduction – It is a measure to investigate into the incident of genetic diseases by testing apparently healty individual in order to control genetic disorders effectively. It has immense implications for controlling genetic disorders.

It is one of the fastest moving field in medical science & became an important part of public health programs in developed countries.

Genetic screening – is a use of specific assays to determine the genetic status of a target populations, those which are at risk for a particular genetic disorder.

Tools applied in Genetic Screening

Pedigree analysis
Karyotyping e.g Down’s Syndrome
Using genetic markers i.e RFLP e.g Sickle Cell Anemia
Prenatal Diagnosis

Conditions / Criteria of Screening Test

The test must be acceptable ( Co-operation of people necessary )
Repeatable ; For reliablity or precision
Validity ; for testing accuracy
Acceptable rates of sensitivity, specificity, false negative & false positive
Effective therapy is available & safety , ease of administration
Sufficient benefit must be deprived from the program to justify the cost : cost effective

Features of Genetic Screening

Done on apparently health individuals
Applied to groups
Test results are arbitrary & final
Less accuracy (Specificity is less) ; more sensitivity
Less expensive
The initiative comes from the investigator or agency providing health care.

Type of Sceening

on Basis of number

Mass Screening – Screening for whole population or sub group
High risk / Selective Screening (Heterozygote Screening)- Applied to high risk groups, groups defined on the basis of research; there is high frequency of heterozygotes in certain population susceptible to certain disorders.
- By screening can determine carrier & help the couple to make informed reproductive choices.
- Eg. Tay Sachs in Ashkenazic Jews, Sickle cells anaemia in blacks, Thalassemia in various ethnic groups
Multiple Screening / Multiphasic Screening – Application of 2 or more tests in combination to a large no. of people at one time rather than carrying out separate test for single diseases.
- It is very much popular in USA & UK

On basis of Subject

Carrier Screening
- Involves testing prospective parents for diseases that they show no symptoms of, but may carry a recessive gene for.
- A blood sample or cheek cell sample is analysed to determine whether either parent carries a faulty gene.
- It both parents carry a specific faulty gene, the chance of the fetus reciving the gene from both parents in 25% & the chance of being a carrier is 50%
- If both parents carry a faulty gene, they may decide to have prenataly testing on the fetus.
Pre-natal Screening – indicates – Maternal age more than 35, family history of a disorder, Abnormal maternal serum screening results, complications pregnancy
- Methods – Amniocentesis, chronic villus sampling, cord blood, maternal blood sampling, ultrasound & X-ray.
- Amniocentesis is used to extract fetal cells (possible about 2 months of conception)
  - Antenatal Diagonis – The cultured fetal cells may be used for detemining their karyotype, levels of critical enzymes & restriction patterns of DNA
  - Unfortunately misused for selective abortion of one sex
- This can detect a disorder before a baby is born
- If diagnosed early in the pregnancy, there is still the possibility of abortion
- Prenatal screening is sometimes seen as controversial.
New-born Screening – to detect certain common disorders so as to initiate treatment early e.g phenylketonuria – special diet, galactosaemic → special diet ; hypothyroidism – replacement therapy
- In most of the USA, newborn screening is mandarory, unless parents have religious objection to it.

Other Types of Screening

Pre-implantation Screening – Screening embryos fertilised by IVF before they are implanted into the uterus.
Pre-symptomatic Screening – appropriate for persons with a family history of a dominantly inherited disorder. Identifying a definite carrier may allow patient to make informed decision e.g Monitoring in case of breast cancer.
- Screening to predict adult onset diseases such Huntington’s disease or adult polycystic kidney disease.
- Screening to estimate the risk of developing cancer or Alzheimer’s disease as an adult
Forensic / Identity Testing – Screening to eg. determine the father of an individual (paternity test)

Significance of Genetic Screening

Case detection (Prescriptive Screening) – Helps in detection of unrecognized genetic diseases e.g. PKU
Control of diseases (Prospective screening) – leads to early diagnosis, permits some effective treatment & reduces the incidence of genetic diseases. Eg. Sickle cell anemia, hemophilia
Educational Opportunities – Provides opportunity to create public awareness & educating health professionals

Case study

In India, new-born screening programmes for sickle cell disorders among tribal and non-tribal populations have recently been initiated in south Gujarat, Maharashtra, Chhattisgarh, Odisha and Madhya Pradesh.
A cross-section of 15 major tribal communities from different parts of Odisha was randomly screened for haemoglobin variants and G6PD deficiency and high frequencies of sickle cell haemoglobinopathy (0-22.4%) and G6PD deficiency (4.3 to 17.4%) were found.
Among the 14 primitive tribal populations from four different States showing a high frequency of sickle gene, the prevalence of G6PD deficiency varied from 0.7 to 15.6 per cent.
The Indian Council of Medical Research and the National Rural Health Mission in different States are undertaking outreach programmes for better management and control of genetic disease.
The tribal groups with a high prevalence of HbS (20-35 %) include the Bhils, Madias, Pawaras, Pardhans and Otkars.
The entire tribal population of 1,25,000 individuals in the Wayanad district of Kerala was screened, followed by genetic counselling where carriers of HbS were advised not to marry carriers

Problems (also for Genetic counselling)

Mistaken Paternity
Problem of confidentiality (professional secrecy) –
- Ex – USA’s genetic information on Non-discrimination Act prohibits health insures denying coverage due to genetic predisposition of disease & demanding more premium.
Difficulties in interpreting the genetic analysis
- Ex – Israel’s ‘Law of Return’ uses DNA testing to determine eligible persons for immigration.
Failure to differentiate b/w neutral polymorphism & a disease state
Delayed counselling
It is often followed with the advice for abortion, which is undesirable to many
In India, genetic screening is very expensive & painstaking process, mainly due to our dependence on European genetic panels.

Conclusion – Thus, genetic screening has immense potential but has been overburdened with challenges such as acceptablity cost, & awareness : particularly in developing & poor countries. In India, once indigenously developed panels are available, genetic screening will become more cost – effective & efficient to India.

Genetic Counselling

Introduction – As per the American Society of Human genetics, genetic counselling is a communication process which deals with the human problems associated with the risk of occurrence of a genetic disorder in a family.

It Consists of educating prospective parents either suffering from / suspected of heterozygous for some genetic disease on risk of their children suffering from same disease.

Genetic Diseases & Genetic Counselling

Genetic counselling is possible for a significant no of diseases. There are

Autosomal Dominant – Achondroplasia, Huntigton’s chorea, Brachydactyly, Marfan’s Syndrome
Autosomal Recessive – Fibrocystic disease of pancreas ; PKU ; Albinism ; Alkaptonuria ; Sickle cell Anemia
Sex -Linked Recessive : Hemphill A&B ; colour blindness ; hydrocephalus etc
Sex-linked Dominant : Vitamin D resistant rickets, blood group -Xg.
Some Non- hereditary Genetic Diseasecan also be counselled for are – Down’s, Patau’s, Klinefelter’s, Edward’s Syndromes etc

Tools for Diagnosis of Genetic Disease

Amniocentesis – prenatal diagnosis upto 14th week ;
Biochemical analysis of fluid
Pedigree Analysis

Types of Genetic counselling:

Prospective genetic counselling:
- allows for true prevention of disease.
- requires identifying heterozygous individual for any particular defect by screening process & explain them the risk of their having affected children if they marry another heterozygous for the same gene.
- e.g. in case of sickle cell anemia, thalassemia.
Retrospective genetic counselling
- When the hereditary disorder has already occurred within the family.
- The methods which could be suggested under retrospective counselling are contraception, pregnancy termination, sterilization depending upon the attitude & culture of the couples

Stages of Genetic Counselling

Pre counselling Assessment
1. Family history diagnosis : Pedigree – a study of the medical history of proband (affected Individual) is obtained & the pedigree is constructed
2. Genetic Screening – blood samples are sent for bio-chemical & molecules tests
3. Prognosis & Diagnosis – pedigree & test results enable the geneticist to confirm or discard any disorder, & check for the mode of inheritance (can be autosomal or sex linked dominant or recessive)
- Recurrence Risk Estimation – Calculating likelihood of recurrence of such genetic disorder in a family
Counselling Interview
- The geneticist conveys the results It a disorder is confirmed, details the associated physical, socio-economic & psychological disabilities.
- Recurrence risk treatment if available, preventive measures including ; pre-natal diagnosis etc should to told to Counselee
Follow Up : Management of disorder curative or supportive– written report to referring physican & consultant, reference to appropriate Heath care agencies, self -help organisation , psychotherapist as required. Counsellor
- Pre-Natal Treatment
  - Termination
  - Steroid treatment – dexamethasone in adrenal hyperplasia
  - Transfusion of stem cells – in immune deficiencies
  - Utero gene therapy / embryo therapy may become possible in future
- Post – Natal Treatment
  - Replacement of gene product e.g – recombinant factor VII (in Haemophila), insulin, Growth harmonon, thyroxine
  - Treatment with drugs – e.g Wilson’s disease → pencillamine
  - Tissue removal & transplantation e.g hereditary spherocytosis → splenectomy ; polycystic kidney
  - Dietary restriction e.g PKU, galactosmia, hypercholesterolemic, lactose deficiency, Folic Acid supplementation etc
  - Gene therapy
  - Stem cell transplantation

Ex – cleft lip is an autosomal dominant disease present at birth itself. The advice in this case is getting a plastic surgery, as it is not a hereditary disease.

Rules for genetic counselling

To advice on the basis of the best & latest genetic information.
Careful record of the proband, where all members normal or otherwise must be recorded.
Exact diagnosis to differentiate b/w genetic disease and a phenotypically similar condition.
Avoidance of value judgment: Advise the parties concerned, of the facts and degrees involved. The final decision should be made by those involved in the ease.
Personal opinion has no room.

Importance or Significance of Genetic Counselling

Getting rid of defective foetus by abortion e.g if with Down’s, Edward’s
Identification of carriers & thereby preventing hereditary diseases
Treatment of genetic disease with partial / complete success e.g Low diet in Phenylalanine as treatment for PKU affected ; anti hemophilia by administering anti-haemolytic globulin

Genetic counselling & antenatal diagnosis definitely are a relief to parents & reduce the frequency of genetically defective individuals in population

However, there are some issues

Heterozygosity – Most genetic defects are recessive. Even if there is a total ban on reproduction by homozygotes, they would remain in population thr heterozygotes
Mistaken paternity
Delayed conseling
Issues of Confidentiality
Screening as asymptote like relative
Difficulty in counseling late developing diseases.

WHO Survey & Recommendation : Genetic Counselling

A survey carried out by WHO showed that a genetic advice was chiefly sort in connection in which congenital abnormalities, psychic illness, inborn errors of metabolism and mental retardation and only a few sought pre-marital advice.
WHO recommends establishment of genetic counselling centers in sufficient number of regions where infectious and nutritional diseases have been brought down under control & in areas where genetic disorders have always posed a serious public health problem.

Treatment for correcting Genetic Disorders

It has been advocated that defective genes may be corrected thr sophisticated genetic techniques / Gene Therapy either during the early stages of embryo development (embryo Therapy) or in specific tissues of the adult patient (Patient Therapy). Such approach is referred is referred to as genetic surgery.
Suggestion has also been made to use highly specific chemical mutagens that will correct the defect in the concerned gene. It is difficult.

Case Study

In western coast of India genetic disorders are found among the fishing community, probably due to radiation from the sand or due to release of radioactive radiation/waste from the nuclear plant. For this reason the department of BioTechnology had started a special drive of genetic counselling
Study in Japan between 1995-2005 → increase abnormalities from 2% to 3% due to nuclear bomb→ regular screening and counselling done
Study among Taivalol moiety in the Todas indicate increase mental retardation from 3% to 6% need to be addressed by genetic counselling
Tribal welfare ministry study undertaken to study the occurrence of down’s syndrome in Sugali’s in Maharashtra & M.P. Similar studies are proposed for tribes with a culture of marrying within the phratry & moiety.

Conclusion – The present scope of genetic counselling is limited to surgery or advice in most cases. However, with recent advancement in gene therapy such as CRISPER – Ca9 technology, future scope looks bright; but still its better to prevented genetic disease by early & appropriate diagnosis. Thus , Genetic counselling should be promoted by creating awareness about genetic diseases.

Human DNA Profiling

Introduction – It is a procedure of developing DNA profile for human identification i.e determining nucleotide sequences of certain areas of DNA which are unique to each individual (except identical twins). It is aka DNA fingerprinting or DNA typing/genotyping / testing. This DNA fingerprinting technique was invented by Alec Jeffreys (1984) at Leicester University, UK

The fingers prints are nothing but a bands of DNA of varying molecular weights that vary from individual to individual.

Characteristics of FP

No two persons have same finger print except identical twins
DNA of an individual give the same pattern throughout from birth to death
Number of FPs (bands) depend on the type of restriction enzyme, probe or both.

Principle & Background –It is based on DNA sequence polymorphism that occur in every organism’s genome.

The chemical str. of everyone’s DNA is the same. The only difference b/w any organism is the order or sequence of the base pairs.
Instead of analyzing whole base pairs sequence, Scientists are able to use a shorter method, b/c of repeating patterns in DNA c/a VNTRs which are k/n vary among individuals a great deal.
- VNTRs are hereditary & hence unique
These patterns don’t, give an individual fingerprint, but they are able to determine whether two DNA samples are from the same person, related people, or non related people.
A minisatellite DNA sequence at a specific chromosome location can have different lengths in different individuals. This variability is due to either a gain or a loss of tandem repeats, probably during DNA replication.
These changes don’t have any biological effect b/c minisatellite DNA doesn’t encode any proteins.
Unrelated individuals generally have minisatellite that differ in length, but children inherit one set of minisatellite DNA sequence from each parent.

Procedure : Steps taken in DNA finger Printing

Performing Southern Blot
- The DNA is extracted from the nuclei of white blood cells or of spermatozoa or of the hair follicle cells that cling to the roots of hairs that have fallen, or been pulled out.
- The DNA molecules are first broken with the help of enzyme restriction endonuclease (called chemical knife) that cuts them into fragments. The fragments of DNA also contain the VNTRs.
- Fragments are separated on an agarose gel and transferred by blotting them onto a nylon membrane.
Making a Radioactive Probe
- four or five separate labelled minisatellite DNA probes, each of which recognizes a distinct DNA sequence.
Creating Hybridization Reaction
- The membrane is hybridized sequentially with four or five separate labelled minisatellite DNA probes, each of which recognizes a distinct DNA sequence. Before next probe is used , the first probe is completely removed(stripped) from the membrane.
- Hybridization is the coming together, or binding, of two genetic sequences. The binding occurs because of the hydrogen bond b/w base pairs
VNTRs
- After each hybridization reaction ,the bands in which the probe has bound to digested DNA samples are visualized by autoradiography
- An X-ray film is exposed to the nylon membrane to mark the places where the radioactive DNA probes have bound to the DNA fragments.
- These places are marked as dark bands when X-ray film is developed. This is known as autoradiography.

Because of the extensive variability in human minisatellite DNA sequences, the chance of finding two individuals in the population with the same DNA fingerfrint is about 1 in 103 to 1 in 108 Therefore , individuals’ DNA banding patterns based on minisatellite DNA sequences are almost as unique as their fingerprints.

Advantage

It is an absolute technique for identification
The establishment of a laboratory for DNA fingerprinting is not a costly affair.

Problems with Genetic Finger Printing

Lack of awareness about the technology
Lack of availability of probes.
With the present knowledge & understanding it is difficult to take the technique to common man.
Presently infrastructure is lacking in India – Only 15 DNA profiling labs in India.
Blood transfusion & bones narrow transplant cases – DNA profiling changes
DNA chimera – multiple genomes.
Generating high probability is necessary to identity the person, especially in criminal cases & paternity test
Errors in hybridisation, probing & amplifying DNA can cause problems specially in medico legal cases.

Practical Application of DNA Fingerprinting

Medico – legal cases
- Identification of Peron – Like skin finger printing (der- matoglyphics), DNA finger printing can help to distinguish one human being from another with exception of monozygotic twins.
- Paternity / Maternity Disputes – DNA finger print-ing can identify the real genetic mother, father and the offspring.
- Criminal identification & Forensic – it has proved that Dhanu, the human bomb, was the real murderer of Shri Rajiv Gandhi
Human Lineage – DNA from various probables is being studied to find out human lineage.
Hereditary Diseases – The technique is being used to identify genes connected with hereditary diseases.
In medicine, DNA fingerprinting has application in genetic counselling, tracing the frequency of donor cells in bone marrow transplant, tissue culture, cell line identification etc.
In case of animal husbandry, proof of parentage, poaching, identified bodies (forensic use ) e.g Suddam Hussain
Similarly identifications of plant varieties for patent parentage & trait markers purposes, micro organism strain are equivocal with DNA fingerprint
Verifying whether hopeful immigrant is as he/she claims is close relative of the already established resident or not.
Anthropological studies – It can identify racial groups, their origin, historical migration and invasions.
- Genography is the study of migratory history of human species.

Conclusion – New DNA Profile bill of govt. of India is a step on the direction of legal recognition of DNA profile as evidence in court of law. Thus towards recognising its importance.

Gene Mapping

Introduction – Gene mapping describes the methods used to identify the locus of a gene & the distance b/w genes.

Gene maps help describe the spatial arrangement of genes on a chromosome i.e which gene is located on which chromosome.
Gene mapping is based on genetic markers on their respective position on the genome.
Gene maps are prepared by collecting samples. Scientists isolate DNA then, they compare the diseased DNA marker with healthy DNA marker.

Types

Genetic or Linkage Mapping – it shows the position of genes relative to each other in terms of recombination frequency.
- Recombination frequency is a measure of the probability of segregation of two genes during crossing over in meiosis.
- Greater recombination frequency b/w two genes means greater chance of segregation during meiosis, thus implying greater distance b/w the genes on the chromosome (and vice versa)
Cytogenetic Map – Based on banding technique, which is definite & microscopically visible.
Physical Map – Uses molecular biology techniques to examine DNA molecules directly in order to construct maps showing the position of genes. Here genes are mapped in terms of base – bair distances.
- This is of two further types
  - Restriction Mapping
  - Contig Mapping
- Ex – Fragmentation of Genome – achieved by restriction enzyme & separated by gel electrophoresis

Advantages of gene mapping

As genes are responsible for all anatomical and physiological. Characteristics of a species – This study is helpful for diagnosis, therapy and prevention.
Used for gene therapy ,Eugenics etc
Helps ↑ the efficacy of genetic counselling & gene therapy, by better diagnosis of diseases, along with targeting of therapeutic targets.
Provides the basis for genome sequencing projects like the Human genome project
Aids in Evolutionary studies of human & their ancestors
Knowledge of the genetic maps of plants & animals has huge agricultural applications.
Is used extensively in forensic anthropology

Case study – The Genographic Project (2005-2015) called as Geno 2.0 by Dr. Spencer wells in collaboration with National Geographic society and IBM is a multiyear genetic anthropology study that aims to map historical human migration patterns by collecting and analyzing DNA samples of over 140 countries.

Conclusion – Genetic mapping becomes more accurate & detailed as the knowledge of a particular genome increases. Thus, genetic map is not a final product, but a work in progress.

Genome Study

Genomics – is the study of genomes,the complete information carried by an individual or the range of genes found in a given species. (3 billion base pairs)

It involves the sequencing & analysing the genomes.
Genomics is also concerned with the structure, function, comparison & evolution of genomes.
Genomics uses DNA sequencing & Bioinformatics to assemble, analyse the function & structure of entire genome.
National Human genome Research Institute (NHGRS) is conducting HGP (human genome Project)

Human Genome Mapping

Human genome mapping means a detailed & schematic description of structural & functional organization of all the chromosomes in the genome of human.
It consists of determining the location of all genes & sequencing the entire genome.
Human genome’s mapping can serve several biomedical purposes.

Methods of Human Genomic Mapping – As designed cross can’t be produced for socio-cultural implication & long life span of the human being. So following three methods are being used

Family Pedigree Data by Linkage Mapping
- The X chromosomes from maternal grandfather without undergoing any recombination passes to mother where it undergoes recombination, to be identified in children.
- Recombinant & non recombinant chromosomes can be identified in children by DNA makers.
- From the data, gene distances, linear order of genes can be established.
- This method has been applied in Japan & Consequently linkage map of human X chromosomes are prepared.
Somatic Cells Hybridization
- Hybrids of somatic cells eg. Mouse & human cells can be produced by Sendai virus cell.
- In such hybrid cells, some human chromosomes are eliminated as hybrid cells divide & some of the human chromosomes are retained. Each of these cells contains a full set of mouse chromosomes but only some of the human set.
- Under such conditions the loss of specific human chromosomes can be studied by Karyotype so that by relating it to the loss of specific function a gene can be located on the missing chromosomes or its specific segment.
Chromosome Banding Techniques – chromosome are best visible during metaphase of mitosis cell division when they arrange at equator. → cell taken at this stage from bone marrow → to fix here ; application of colchicine → cell stationed to get banding pattern. There are many types of staining procedures
- Q – Banding / Quinacrine Fluorescence banding
- G – Banding / Giemsa banding
- C – Banding / Centro metic banding
- R – Banding / Reverse banding

The different banding techniques stain different parts of chromosomes; these techniques of staining have permitted the mapping of genes on the chromosomes. Missing portions of chromosomes seen in terms of absent bands can be correlated with the absence of a specific trait.

Sequencing the Genome : the overall approach referred to as hierarchical short gun sequencing is summarised below

Human Genome Project

Introduction – An international effort is going on the Human genome mapping since 1990.

HGP was officially stated in Oct, 1990 in USA ; sponsored by Dept. of Energy (DOE) & National Institute of Health (NIH).

Human genome project (HGP) was an international scientific research project which got successfully completed in the year 2003 by sequencing the entire human genome of 3.3 billion base pairs. The HGP led to the growth of bioinformatics which is a vast field of research. The successful sequencing of the human genome could solve the mystery of many disorders in humans and gave us a way to cope up with them

Goal of HGP

Map the entire human genome
Determine the complete sequence of the 3 billion base pair
Identify all the genes in human DNA
Store this info. in database
Develop tools for data analysis
Address the ethical, legal & social issues (ELSI) resulting from the project.

Methods of HGP – In this project, two different & significant methods are typically used.

Expressed sequence tags wherein the genes were differentiated into the ones forming a part of the genome and the others which expressed RNAs.
Sequence Annotation wherein the entire genome was first sequenced and the functional tags were assigned later.

Process of HGP

The complete gene set was isolated from a cell.
It was then split into small fragments.
This DNA structure was then amplified with the help of a vector which mostly was BAC (Bacterial artificial chromosomes) & YAC (Yeast artificial chromosomes).
The smaller fragments were then sequenced using DNA sequencers.
On the basis of overlapping regions, the sequences were then arranged.
All the information of this genome sequence was then stored in a computer-based program.
This way the entire genome was sequenced and stored as genome database in computers.
Genome mapping was the next goal which was achieved with the help of microsatellites (repetitive DNA sequences).

Features of the Human genome project include:

Our entire genome is made up of 3164.7 million base pairs.
On average, a gene is made up of 3000 nucleotides.
The function of more than 50 percent of the genes is yet to be discovered.
Proteins are coded by less than 2 percent of the genome.
Most of the genome is made up of repetitive sequences which have no coding purposes specifically but such redundant codes can help us better understand of genetic development of humanity through the ages.

Human Genome Report – first analysis if the entire set of human genetic instruction – The Human Genome Report – was public on February 11, 2011. The following are its main observations –

On Human Diversity – every person shares 99.99 % of his/her genetic code with all others, irrespective of their ethnic differences. This finding once & for all busts the muth fo racial superiority, as genetic variation of 0.01% is clearly not enough for creating racial categories.
On Medicine – All current drugs on market are based on just 483 biological targets in the human body. The report has now revealed hundreds of thousand more. This will open new frontier in genetic counselling & gene therapy.
On Evolution – Hundreds of human genes appear to have been exchanged with bacteria at some point in evolution. Humans also share many genes with organisms like fruit fly, nematode worm & yeast. This makes us appreciate out humble origins & the beauty of evolution.

Application of HGP

has stimulated & promoted the development of new biotechnology.
Greater insight into aetiology of disease
Earlier detection, prevention and treatment by gene therapy of various genetic disorders.
DNA Forensics (Identification) – CODIS combined DNA index system – helps analysis of human genome from a small sample of DNA in forensics.
Comparative DNA sequences Analysis ; New avenues in study of theory of Evolution
- Trace migrations & origins of populations
- Relation b/w population
Studying other organism will help ascertain function of unknown genes, insights into evolution & b/w 3 kingdoms.
Anthropology
- Human genome diversity project aims at mapping the DNA that varies between ethnic groups.
- The project could unlock secretes behind & create new strategies for managing the vulnerability of ethnic groups to certain diseases
- It could also show that how human populations have adapted to these vulnerabilities.
Psychological Disorder – Studies of gene involved in behavior may lead to new insights into causation & positive treatment of psychological disorders.
Tailor Made drugs – These can be prepared to accommodate the variations in the enzymes & other protein in drug action & metabolism found among individuals.
DNA Probe – Probes for any genes will be available if needed, leading to improved diagnostic testing for disease susceptible genes & for genes directly involving causation of specific disease.
GM crops & Animals
Bacterial Genome – Energy production, remediation etc
Bio pesticides

Criticism

It was viewed as water of time, money & Human Resources on a monotonous technology driven exercise
World divert funds from already sparsely funded small individual science projects
Complete sequence is unnecessary & tedious
Most part my be just evolutionary baggage without function
ELSI – Ethical Legal Social Issue
- Access to genetic info is an issue ; if handled carelessly could cause discrimination by potential employees & even govt
- Privacy & confidentiality of information
- Risk of anxiety & unwelcome stigmatisation
- Patenting of products of HGP

Thus, the HGP is immense utility to anthropologists. For biological anthropologists, it can be used in the field of medicine, and aid in evolutionary studies of human & their ancestors For Socio-cultural Anthropologists, it will enable them to completely discard racial studies once & for all from Anthropology.

HGP – Write Project was initiated in 2016 .

It aims at improving the ability to chemically manipulate DNA, and ultimately synthetically create an entire human genome.
Is an extension of genome projects, now to include development of technologies for synthesis & testing of many genomes of microbe, plants & animals
These leverages two decades of work on synthesis biology & artificial gene synthesis

National Institute of Health (NIH),

By 2018, completes in depth genomic analysis of 33 cancer type (10,000 Tumors)

Neanderthal Genome Project

Collaboration of scientists to sequence the Neanderthal genome
Is is co-ordinated by the Max Plank Institute for evolutionary anthropology in Germany.
Neanderthal DNA – 99.7 % ; Chimpanzee – 98.8 %

Bacterial Genome – Energy production, remediation etc
- Waste Control & Environmental Cleanup
  - In 1994, the Microbial Genome Initiative was formulated to sequence the genomes of bacteria useful in the areas of energy production, environmental remediation, toxic waste reduction, and industrial processing.
  - Resulting from that project, six microbes that live under extreme temperature and pressure conditions have been sequenced.
  - By learning the unique protein structure of these microbes, it may be possible to use the organisms and their enzymes for such practical purposes as waste control and environmental cleanup
  - Energy Sources: Biotechnology will be important in improving the use of fossil-based resources.
    - Increased energy demands require strategies to circumvent the many problems with today’s dominant energy technologies
    - Biotechnology will help address these needs by providing a cleaner means for the bioconversion of raw materials to refined products.
    - Additionally, there is the possibility of developing entirely new biomass-based energy sources. Having the genomic sequence of the methane-producing microorganism.

latest Law & Updates about Gene therapy ; National Guidelines –

https://www.notion.so/Gene-Therapy-GT-Product-National-Guidelines-0b11611bdf0b490187f213f3ff22809b

Genome India Project

Next Generation Sequencing (NSG) Facility

DNA day is celebrated on April 25.

Down’s Syndrome / Mongoloid Syndrome	Patau Syndrome	Edward Syndrome	Cri Du Chat Syndrome
• Named after Landon Down (1886)
Diagram from Aksit’s book
• Trisomy 21 ; additional can occur by Non Disjunction & TranslocatN• Karyotype – (47, +21) • syndrome finds pseudo resemblance with typical mongoloid features so k/n as Mongoloid s too • with ↑ in age of mother, incident of it drastically ↑ → b/c disjunction seem to be common in aged ♀• Frequency – 1 per 700 live births, but in Caucasoid it is ↑ up to 3 per 200 live births	• Trisomy 13 (47, +13)• Can also be mosaicim• per 2200 live births. There is moderate maternal age effect in Patau’s Syndrome	• Trisomy 18 (47, +18)• per 4500 live births. • 80% patients are females• Incidence increase wth mother’s age Striking & diagnostic Features • Small triangular mouth & flexed fingers	• Deletion aberration on Chromosome 5 on p-arm• Karyotype (46, XX) 5p • few families show balanced translocation where parent who normal but some of his offspring inherit deleted chromosome & are affected • frequency of syndrome – Not available
General Features
• child is flaccid & shows hypotonia or low muscle tone • child doesn’t cry much in newborn period • short stature (4 ft)• hands are short & stubby• palm peculiar features • +nce of Simian Crease at time of brith • Tri – Radius near centre • -nce of pattern in thenar Area• digital loop b/w 3rd & 4th digits • tendency for every finger to have a loop in the print region	• decreased muscle tone • skeletal (limb) abnormalities • Extra fingers or toe (polydactyl) • clenched hands (with outer fingers on top of the inner fingers) • single palmar crease	• low birth weight • flexed hand & clinched fingers • fingers curled over one another in clenched fists – 2nd & 5th digits show overlap with the 3rd & 4th digits • arches on 6 or more fingers in fingerprint • deformities of feet • Malformations of intestine	• high pitched cry sound like cat • low birth weight & slow growth • single line in the palm of the hand (Simian Crease)• Partial webbing or fussing of fingers or toes
Face
• Small skull, flattened nose, broad & round face, upward sainting eyes • Epicanthic fold on the eyelid• Iris shows speckles around margins • white spots on the coloured part of the eye / shortsightedness (myopia) & deadness • Excess skin at the nap of neck • ears are small & dysplasic • Large tongues with distinctive furrowing	• cleft lip or palate • Small lower Jaw (Micrognathia) • slopping forehead & deformed appearance of the face • close set eyes – eyes may actually fuse together into one • hole, spit or cleft in the iris • low set ears	• abnormally small head – Microcephaly (small head & Brain) • deformities of skull, face & teeth • small & receding lower jaw • small triangular mount• Mal formed & low set ears	• Small head (microcephaly) • Outward & downward slant to the eyes• Excessively wide spaced eyes• Broad face & flat nose• Small jaw (micrognathia) • Low set or abnormally shaped ears
Intelligence
• small head (microcephalic) • Mental Retardation, severe	• small head (microcephaly )• mental repartition, server	• Small head, mental development not complete	• Sever Mental retardation, IQ 20-40• Slow or incomplete development of motor skills
Health & Life Expectancy
• Congenital heart malformations • eye & kidney defects are common • Neutrophils show sessile projections in nucleus • Persistent elevation of HbF & significant decrease in HbA2 concn during the first few months of life• Seizures • Gross malformation of brain• Such individuals die within hours or days after birth however some are able to survive for few months ( mean survival time is 132 days)• Life expectancy can be high as 40-50 years & there is no effect on fertility	• Congenital heart malformations • eye & kidney defects are common • Neutrophils show sessile projections in nucleus • Persistent elevation of HbF & significant decrease in HbA2 concn during the first few months of life• Seizures • Gross malformation of brain• Such individuals die within hours or days after birth however some are able to survive for few months ( mean survival time is 132 days)	• congenital heart defects • heart defects, kidney abnormalities • spina bifida • Syndactyly• Groin Hernia• Life expectancy very low. Most of the Trisomy 18 babies abort spontaneously mean survival time is 102 days. Approximately 50 % of the total survive for 2 months • Female survive better than males.	• Child almost fails to thrive, a few that survive & live long have severe mental retardation