Sex Determination and Linkage[Yq-Rupendra Shrestha]

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SEX DETERMINATION AND LINKAGE SRI RAMACHANDRA UNIVERSITY PORUR, CHENNAI – 600 116 DEPARTMENT OF HUMAN GENETICS Mr. RUPENDRA SHRESTHA Department of Human Genetics/2012/S.Rupendra

The inheritance of gender :

The inheritance of gender Is it going to be a boy or a girl? © University of New Mexico Department of Human Genetics/2012/S.Rupendra

Background:

Background Latin word Sexus meaning section or separation. Sex Department of Human Genetics/2012/S.Rupendra

INTRODUCTION::

INTRODUCTION: The development of an organism into male or female is called SEX DETERMINATION . In man sex - determined by three main factors: Chromosomes Barr body Hormones Department of Human Genetics/2012/S.Rupendra

DISCOVERY OF SEX CHROMOSOME:

DISCOVERY OF SEX CHROMOSOME 1902, Clarance McClung , The American geneticist, had work on gametogenesis of grasshopper and suggest that X body is involved in determination of sex some or other way... He showed that the somatic cell of female grasshopper contain 24 chromosome whereas the male contains only 23 chromosome Department of Human Genetics/2012/S.Rupendra

SEX DETERMINATION BY CHROMOSOMES:

SEX DETERMINATION BY CHROMOSOMES The determination of sex by chromosomes is – Chromosomal theory of sex determination . Female – two X chromosomes ( Homogametic ) Males – one X and one Y chromosome (Heterogamesis). Sex is determined by sperm. Department of Human Genetics/2012/S.Rupendra

SEX DETERMINATION BY BARR BODY:

SEX DETERMINATION BY BARR BODY Darkly stained inactivated X chromosomes (nucleolus in nerve cells, nuclear membrane of oral mucosa, nucleoplasm in neurons after electric stimulation and nuclear expansion)– Barr Body Discovered by BARR and BERTRRAM (1949). Also called sex chromatin Sex determined by presence or absence of Barr body Male – no Barr body Female – 1 Barr body Department of Human Genetics/2012/S.Rupendra

BARR BODY:

BARR BODY Department of Human Genetics/2012/S.Rupendra

X - INACTIVATION:

X - INACTIVATION The inactive X chromosome b ecomes condensed and attaches to the inside of the nuclear envelope- Barr Body . Most genes are NOT expressed . Barr Body Chromosomes are reactivated in ovary cell s --> ova. Department of Human Genetics/2012/S.Rupendra

X - INACTIVATION:

X - INACTIVATION Mary Lyon - showed that the selection of which X will become the Barr body is random and independent in each embryonic cell present at the time of X-inactivation . After the X is inactive in a particular cell, all the mitotic descendents of that cell have the same X inactivated . Department of Human Genetics/2012/S.Rupendra

MECHANISM OF X INACTIVATION :

MECHANISM OF X INACTIVATION Attachment of CH 3 groups to cytosine. A gene is active only on the Barr body chromosome - XIST (X-inactive specific transcript) - encodes an RNA . These RNA molecules bind to the chromosome from which they were made. But which X will have an active XIST gene ? Unknown! Department of Human Genetics/2012/S.Rupendra

FEMALES ARE PROTEIN MOSAICS:

FEMALES ARE PROTEIN MOSAICS Mosaics - half of her cells have the active X derived from the mother , half of her cells have the active X from the father . If heterozygous , the same tissue will express one allele from one X chromosome and another allele from the other X chromosome Department of Human Genetics/2012/S.Rupendra

Calico Cats- An Example of Mosaicism:

Calico Cats- An Example of Mosaicism Department of Human Genetics/2012/S.Rupendra

SEX DETERMINATION BY HORMONES:

SEX DETERMINATION BY HORMONES In man sex is regulated by Hormones. Sex reversal – Hormonal unbalance. Testes removed before puberty – female characters develop. Tumors of Adrenal in women – Masculine characters Department of Human Genetics/2012/S.Rupendra

SEX CHROMOSOMES :

SEX CHROMOSOMES Department of Human Genetics/2012/S.Rupendra

SEX DETERMINATION IN HUMAN BEINGS:

SEX DETERMINATION IN HUMAN BEINGS 46 Total (23 pair) Autosomes - 22 pair are perfectly matched- autosomes . Sex chromosomes Remaining one pair- sex chromosomes . Human: XX normal female XY normal male Y chromosome highly condensed with a few dozen genes. Department of Human Genetics/2012/S.Rupendra

GAMETOGENESIS:

GAMETOGENESIS 44 + XY 22 + X 22 + Y 44 + XX 22 + X 22 + X Department of Human Genetics/2012/S.Rupendra

CHROMOSOMAL BASIS OF SEX:

CHROMOSOMAL BASIS OF SEX Each ovum contains one X chromosome. Sperm have either X OR the Y chromosome. Department of Human Genetics/2012/S.Rupendra

PowerPoint Presentation:

X AND Y CHROMOSOME Department of Human Genetics/2012/S.Rupendra

CHROMOSOME -X:

CHROMOSOME -X We can live without a Y chromosome (half of us do) but we must have at least one X chromosome largest chromosomes and with 2000 genes & 153 million bp most of genes are unrelated to sex. For example, on the X chromosome (at locus Xq28.2) is the gene for an enzyme called glucose-6-phosphate dehydrogenase . uses to metabolize glucose. other genes on the X chromosome involved in other important events such as DNA recycling, muscle development, immunity and blood clotting. Department of Human Genetics/2012/S.Rupendra

What determines sex in humans?:

What determines sex in humans? Department of Human Genetics/2012/S.Rupendra

ROLE OF Y CHROMOSOME:

ROLE OF Y CHROMOSOME Evidence for the Y chromosome mechanism: Y chromosome confers maleness and determines sex. Verified by studies of non-disjunction aneuploidy : XO “Turner Syndrome” Female Sterile 1/10,000 (most XO fetuses die before birth). Survivors show below average height, poorly developed breasts, and immature sexual organs XXY “Klinefelter Syndrome” Male 1/1000 Above average height, under-developed testes, and breast development in ~50% XYY -Male with above average height, fertility problems. XXX -Female, normal though sometimes less fertile. Department of Human Genetics/2012/ S.Rupendra

ROLE OF Y CHROMOSOME:

ROLE OF Y CHROMOSOME Department of Human Genetics/2012/S.Rupendra

STRUCTURE OF Y CHROMOSOME:

STRUCTURE OF Y CHROMOSOME Department of Human Genetics/2012/S.Rupendra

STRUCTURE OF Y CHROMOSOME:

STRUCTURE OF Y CHROMOSOME Department of Human Genetics/2012/S.Rupendra

STRUCTURE OF Y CHROMOSOME:

STRUCTURE OF Y CHROMOSOME Department of Human Genetics/2012/S.Rupendra

STRUCTURE OF Y CHROMOSOME:

STRUCTURE OF Y CHROMOSOME Department of Human Genetics/2012/S.Rupendra

GENES INVOLVED IN DETERMINATION OF HUMAN MALE SEX:

GENES INVOLVED IN DETERMINATION OF HUMAN MALE SEX SRY gene SOX9 autosomal gene SF1 gene DAX1 gene Department of Human Genetics/2012/S.Rupendra

Molecular pathway for sex determination The biology of infertility: research advance and clinical challenge; Martin et.al; 6 Nov 2008:

Molecular pathway for sex determination T he biology of infertility: research advance and clinical challenge; Martin et.al; 6 N ov 2008 Department of Human Genetics/2012/S.Rupendra

SRY GENE:

SRY GENE Small 79 amino acid intron less gene TDF factor (Testis Determining Factor) A member of the SOX (SRY-related HMG-box) family From Class I SRY genes, which have X chromosome homologues (from which they diverged) Present in a single copy SRY protein contains a domain (HMG box) that binds to DNA at a target sequence and bends it at particular angles Almost all sex-reversing mutations occur in this HMG box Department of Human Genetics/2012/S.Rupendra

PowerPoint Presentation:

Sex reversal - T ranslocation of SRY from Y to X Department of Human Genetics/2012/S.Rupendra

SRY Protein Binding to DNA (Gene Regulation):

SRY Protein Binding to DNA (Gene Regulation) Department of Human Genetics/2012/S.Rupendra

SOX9 AUTOSOMAL GENE:

SOX9 AUTOSOMAL GENE Encodes a putative transcription factor that also contain HMG (High M otility Group) box Acts as sex reversal gene XX human with extra copy of SOX9 - develops as male (Huang et al.,1999) Campomelic Dysplasia (female or hermaphrodites) - only one SOX9 gene Essential for testes formation Department of Human Genetics/2012/S.Rupendra

SF1 GENE:

SF1 GENE Steroidogenic factor 1 SRY protein activate SF1 gene SF1 gene - activate component of male sexual differentiation. Department of Human Genetics/2012/S.Rupendra

DAX1 GENE:

DAX1 GENE Ovary determining gene on X chromosome Bernstein et al. 1980., reported two sisters who are genetically XY Their Y chromosome are normal, duplication of small portion of short arm of X chromosome If two copies of DAX1 region on active X , SRY signal from Y chromosome would be reversed. Department of Human Genetics/2012/S.Rupendra

PARTHENOGENESIS :

PARTHENOGENESIS What about animals like most kinds of wasps, bees, and ants that have no sex chromosomes ? How is gender determined? In these species, fertilization determines gender . If an egg becomes fertilized it will develop into a female . A non-fertilized egg may develop into a male . The female is diploid and contains two sets of chromosomes, while the male is haploid . This development of an unfertilized egg into an individual is called parthenogenesis . Department of Human Genetics/2012/S.Rupendra

COMPOUND SEX CHROMOSOME:

COMPOUND SEX CHROMOSOME X chromosome commonly found as single chromosome or single homologous pair of chromosome In some species, they maintain compounds more than one kind of X chromosome that act together as a sex determining group In Ascaris incurva, autosome – 13 pairs No of compound X chromosome - 8 (8X + A) + (8X + A) = 16 X + 2 A Female Diploid - 42 Sperm Egg (Y + A) + (8X + A) = 8 X + Y+ 2 A M ale Diploid - 35 Sperm Egg Department of Human Genetics/2012/S.Rupendra

COMPOUND SEX CHROMOSOME:

COMPOUND SEX CHROMOSOME The Y chromosome may also exist as a compound chromosome In some both X and Y chromosome may found compound together. E.g. In beetle ( Blaps polychersta ) In male- 12 X In female- 6 Y Department of Human Genetics/2012/S.Rupendra

MEIOTIC BEHAVIOUR OF SEX CHROMOSOME:

MEIOTIC BEHAVIOUR OF SEX CHROMOSOME Department of Human Genetics/2012/S.Rupendra

PowerPoint Presentation:

Nondisjunction in meiosis involving the X chromosome Department of Human Genetics/2012/S.Rupendra

ALTERATION OF CHROMOSOME NUMBERS:

ALTERATION OF CHROMOSOME NUMBERS Primary Nondisjunction - members of a pair of homologous chromosomes do not move apart properly during anaphase of meiosis I. Unequal distribution of chromosomes in the daughter gametes. Department of Human Genetics/2012/S.Rupendra

NON-DISJUNCTION LEADS TO ABNORMAL CHROMOSOME IN ZYGOTE:

NON-DISJUNCTION LEADS TO ABNORMAL CHROMOSOME IN ZYGOTE If the aberrant gamete units with a normal gamete, the offspring will have an abnormal # of chromosomes- aneuploid . Aneuploid : 2n + 1 = Trisomy 2n - 1 = Monosomy Department of Human Genetics/2012/S.Rupendra

MONOSOMICS:

MONOSOMICS Organisms which have lost one copy of a chromosome. Do Not Survive Development! Lethal Error! Department of Human Genetics/2012/S.Rupendra

TRISOMICS:

TRISOMICS Most do not survive either. Some trisomies do survive for a time: Trisomy 13, 15, 18- severe developmental defects, die within a few months. Trisomy 21 - Down Syndrome. Trisomy 22 - mentally retarded. Department of Human Genetics/2012/S.Rupendra

Trisomy 13 Facies- Bilateral Cleft Lip:

Trisomy 13 Facies- Bilateral Cleft Lip Trisomy 18 Syndrome Down’s Syndrome (Trisomy 21) Department of Human Genetics/2012/S.Rupendra

TRISOMY 21 PHENOTYPE:

TRISOMY 21 PHENOTYPE Slower skeletal development- short stature. Below normal I.Q. 11 X more likely for leukemia. Cancer gene located on 21. Often have Alzheimer-like dimentia. Alzheimer gene located on 21. Usually die prematurely. Caused by a nondisjunction event during oogenesis. Department of Human Genetics/2012/S.Rupendra

Trisomy 21 Karyotype:

Trisomy 21 Karyotype Department of Human Genetics/2012/S.Rupendra

NON DIS-JUNCTION OF THE SEX CHROMOSOME:

NON DIS-JUNCTION OF THE SEX CHROMOSOME Two Types: Nondisjunction of the X Chromosome. Nondisjunction of the Y Chromosome. Department of Human Genetics/2012/S.Rupendra

PowerPoint Presentation:

X X X X X Y X Y XXX X XXY Y NON-DISJUNCTION Department of Human Genetics/2012/S.Rupendra

NON-DISJUNCTION OF THE X:

NON-DISJUNCTION OF THE X “Super Females” XXX - Female with one functional X and two Barr bodies; sterile but appears normal. XXY - Klinefelter Syndrome - sterile male with female characteristics, some mental retardation; underdeveloped male characteristics; occurs in 1/ 500 male births. Department of Human Genetics/2012/S.Rupendra

Without an X Chromosome!:

Without an X Chromosome! OY - zygote is inviable ; all humans require at least one copy of the X chromosome. XO - Turner Syndrome- sterile female, short stature, webbed neck, and immature sex organs, lower I.Q.; occurs in 1/ 5,000 female births. Department of Human Genetics/2012/S.Rupendra

NON-DISJUNCTION ALSO OCCURS IN MALE:

NON-DISJUNCTION ALSO OCCURS IN MALE “Super Males” XYY- fertile males of normal appearance; occurs in 1/ 1,000 male births. Historically thought to be 20 X higher in institutionalized males. Not true. Department of Human Genetics/2012/S.Rupendra

SEX LINKAGE:

SEX LINKAGE 1910: Thomas Hunt Morgan (Nobel Prize 1933) Fruit Flies ( Drosophila melanogaster ) http:// nobelprize.org/nobel_prizes/medicine/articles/lewis/index.html © 2007 Paul Billiet ODWS Department of Human Genetics/2012/S.Rupendra

PowerPoint Presentation:

Since both X and Y are sex chromosomes, three different patterns of inheritance are possible, SEX LINKED usually refers to loci found only on the X chromosome ; Y LINKED is used to refer to loci found only on the Y chromosome, which control HOLANDRIC TRAITS ( traits found only in males ). Loci found on both the X and Y chromosomes are called pseudoautosomal. SEX LINKAGE Department of Human Genetics/2012/S.Rupendra

PowerPoint Presentation:

Sex linkage: Experiments with Drosophila demonstrated the chromosome theory of heredity . Discovered a mutant white-eyed male fly ( wild type color is red). Next, crossed wild type female with white-eyed male. All F 1 offspring had red eyes (therefore white is recessive ). Crossed F 1 x F 1  F 2 (3,470 red/782 white ). All white-eyed flies also were male . Morgan hypothesized that eye color gene is located on the X chromosome . Ratio is of white and red-eyed flies 1/4.4 (observed) << 1/3 (expected); white-eyed flies have lower viability. Department of Human Genetics/2012/S.Rupendra

PowerPoint Presentation:

Parental Cross F 1 x F 1 Department of Human Genetics/2012/S.Rupendra

The case of the white-eyed mutant:

The case of the white-eyed mutant Character Traits Eye colour Red eye (wild type) White eye (mutant) P Phenotypes Wild type (red-eyed) female x White-eyed male F 1 Phenotypes All red-eyed Red eye is dominant to white eye © 2007 Paul Billiet ODWS Department of Human Genetics/2012/S.Rupendra

HYPOTHESIS:

HYPOTHESIS A cross between the F 1 flies should give us: 3 red eye : 1 white eye F 2 Phenotypes Red eye White eye Numbers 3470 82% 782 18% So far so good © 2007 Paul Billiet ODWS Department of Human Genetics/2012/S.Rupendra

GENETIC DIAGRAMS FOR SEX LINKED GENES:

GENETIC DIAGRAMS FOR SEX LINKED GENES Character Trait Alleles Eye colour Red eye R White eye r Genotypes Phenotypes X R X R X R X r X r X r X R Y X r Y © 2007 Paul Billiet ODWS Department of Human Genetics/2012/S.Rupendra

GENETIC DIAGRAMS FOR SEX LINKED GENES:

GENETIC DIAGRAMS FOR SEX LINKED GENES Character Trait Alleles Eye colour Red eye R White eye r Genotypes Phenotypes X R X R X R X r X r X r Red-eyed female Red-eyed female White-eyed female X R Y X r Y Red-eyed male White-eyed male © 2007 Paul Billiet ODWS Department of Human Genetics/2012/S.Rupendra

PowerPoint Presentation:

F 2 Phenotypes Females Males Red-eyed White-eyed Red-eyed White-eyed Expected All None 50% 50% Observed 2459 0 1011 782 This gene has its LOCUS on the X-chromosome It is said to be SEX-LINKED © 2007 Paul Billiet ODWS Department of Human Genetics/2012/S.Rupendra

ATTACHED X:

ATTACHED X L.v. Morgan discovered a strains of flies in which 100% non-disjunction occurred. F emales mated to Males carrying sex linked mutated genes , always produced offspring F emale exactly like their mother & M ales exactly like their father A white eyed male crossed to these females , always produced white eye sons but normal daughters... Department of Human Genetics/2012/S.Rupendra

ATTACHED X:

ATTACHED X The inheritance pattern suggested that the female offspring of these crosses received both X’s from their mother, whereas the males received a single X-exactly from their father The production of only nondisjunction offspring by females of this strain was explained as resulting from a physical attachment between both maternal X chromosomes In XXY females X’s were so connected that they were inherited as a unit “Attached X” such females therefore, produced only two types of gametes , XX & Y-bearing eggs Department of Human Genetics/2012/S.Rupendra

ATTACHED X:

ATTACHED X Department of Human Genetics/2012/S.Rupendra

Replication and segregation of attached X- chromosome:

Replication and segregation of attached X- chromosome Department of Human Genetics/2012/S.Rupendra

SEX RATIO:

SEX RATIO Normally, the equal proportion of the male and female gametes formed by the heterogametic sex in a species result in approx. equal proportions of the two sexes at birth. In some case, proportion of the male and female birth are far from equal. Department of Human Genetics/2012/S.Rupendra

SEX RATIO:

SEX RATIO In certain stocks of drosophila in which one of the X-chromosome carries a lethal gene Male inheriting this X- chromosome DIE before emergence as adults. while heterozygote female are fully viable, since they also carry one X- chromosomes bearing normal allele for l…. i.e. l + Department of Human Genetics/2012/S.Rupendra

PowerPoint Presentation:

THANK YOU FOR KIND ATTENTION Department of Human Genetics/2012/S.Rupendra

Rupendra speaks;" More u read ,the more confusion; confusion triggers our curiosity, curiosity on new things is searching for it that’s called research; researcher are honoured as scientists that’s we should aim in life”:

Rupendra speaks;" More u read ,the more confusion; confusion triggers our curiosity , curiosity on new things is searching for it that’s called research ; researcher are honoured as scientists that’s we should aim in life” Department of Human Genetics/2012/S.Rupendra