Mammalian Sex Determination

Mammalian Sex Determination

Overview of mammalian embryonic development:

human embryo development on You Tube by HHMI

Mechanisms of sex determination in animals

female male examples and explanation
XX XY most mammals, including humans; some amphibians, some insects – Y determines maleness
ZW ZZ birds, reptiles, some amphibians – W determines femaleness
XX XY some insects, including Drosophila – X:autosome ratio greater than 0.75 is female, less is male
XX XO hemiptera (true bugs)
diploid haploid honeybees, ants
XX* XO C. elegans – XX is a hermaphrodite, XO is male
XX, XY, YY XX, XY, YY some fish with environmentally determined sex or natural sex reversal in a single individual
XFO XMO Ellobius lutescens (molve-vole) – OO and XX are lethal

Chromosomes and Human Sex Determination

Human sex determined by sex chromosomes:  46XX is normal female, 46XY is normal male.

45XO female, Turner’s syndrome:  short stature, webbing of neck, underdeveloped secondary sexual characteristics, sterile due to degeneration of gametes and ovaries after birth
Turner’s syndrome fully expressed in females lacking short arm of one X.
Lack of proximal part of long arm of X causes gonadal dysgenesis, but not somatic abnormalities.
But how does this fit in with X inactivation?
Both X’s fully functional during oogenesis, may be required for long term maintenance of oocytes in meiotic prophase.
Not all genes on X are inactivated.

47XXX fertile female, generally normal secondary sexual characteristics.  However, more than 3 X’s cause severe mental retardation.

47XXY male, Klinefelter’s syndrome:  sterile, no germ cells, small testes.  Very tall, some are mentally retarded, but wide variation in phenotype, androgen levels.
Also occurs in XXYY, XXXY, XXXXY, XXXXXY – more than one X incompatible with spermatogenesis?  X:autosome translocations cause male sterility, but not female sterility.  XXY mice phenotypically male, but sterile without germ cells.

Development of the Mammalian Reproductive System

Differentiation of ovaries and testes from bipotential gonads

A. Before the embryonic to fetal transition, the gonads and reproductive ducts (Wolffian; blue and Müllerian; red) of the urogenital ridge are bipotential. B. In the presence of the Y chromosome, the gonads of the bipotential urogenital ridge differentiate into testes, which produce both MIS to eliminate the Müllerian ducts and testosterone to stimulate differentiation of the Wolffian ducts into the male internal reproductive tract structures. C. In the absence of SRY, ovaries differentiate, Wolffian ducts degenerate, and Müllerian ducts develop into a simple columnar epithelial tube that will differentiate into the oviducts, uterus, cervix, and upper portion of the vagina. From Texeira et al. Uterine Stem Cells

Reproductive system composed of gonads (ovary or testes), ducts (Mullerian in females, Wolffian in males), and external genitalia (vagina or penis).

Gonad arises from intermediate mesoderm, as bipotential genital ridge.  It contains 3 types of somatic tissues:
supporting cells (Sertoli cells in males, follicle cells in females),
steroidogenic cells (Leydig cells in males, theca cells in females),
connective tissue cells.
Germ cells migrate into gonad at 10.5-12 days p.c. (post-coitum) in mouse.
No visible sex differentiation until 7th week of gestation in humans (11.5-12.5 days p.c. in mouse).

Primary sex differentiation event is gonadal differentiation into ovary or testes.  Germ cells not involved in primary sex determination, because mutants where germ cells do not migrate into gonads, or mutants without germ cells still differentiate female or male gonads. Germ cell differentiation depends on gonadal environment, and requires an RNA-binding protein called DAZL (Gill et al. 2011).

Female differentiation appears to be default pathway:  castrated male rabbit fetuses develop into phenotypic females for both reproductive ducts and external genitals, and female fetuses with ovaries removed still develop into females.  Female fetuses with testes grafts develop into males.

Testicular hormones MIS (Mullerian inhibiting substance; also known as AMH, or anti-Mullerien hormone, yet another member of the TGFbeta superfamily) and testosterone (converted to dihydroxy testosterone) cause male differentiation of the ducts and external genitalia, respectively.

Genetics of Sex Determination

Sxr mice:  XX(sxr) males, XY(sxr) females

H-Y antigen and Ohno’s theory

Sxr’ mice – no HY antigen!

mapping of SRY in region of Y chromosome translocated in sex-reversed individuals

Sex-reversed humans:  XX males, XY females involving X:Y translocations

ZFY- zinc finger protein with 13 zinc finger motifs for DNA binding, and an acidic domain for interaction with transcription factors.
Homologue, ZFX, also present on X chromosome of mammals
Marsupials, with X-Y sex determination, have ZFY homologue on autosome!
Timing of ZFY expression is too late – in testes, but only after testes differentiation has started.
Other sex-reversed XX males have no ZFY!
Original XY female that led to mapping of TDF had multiple deletions.


An XX sex-reversed mouse (33.13) with SRY gene is phenotypically male.

XX mice carrying 14 kb of Y chromosome containing Sry gene develop as phenotypic males – no sperm, but testes have normal hormonal function, normal male secondary sexual diferentiation and mating behavior.

XY mice with Sry deletion develop as phenotypic females, fertile.

XX humans carrying Sry-containing fragments of Y translocated to X are phenotypically male, sterile, but with normal internal and external genitalia.
If translocation is small (35 kb), then abnormal and ambiguous genitalia.
XY humans with mutations in HMG box of Sry are sterile, have poorly developed gonads without clear testicular or ovarian histology, but with no testicular hormones, Mullerien structures persist and get female secondary sexual differentiation.

Sry encodes a member of HMG (high mobility group) family of DNA binding proteins (Lef-1/Tcf, the transcription factors regulated by Wnt signalling, also belong to this group).  Induces DNA bending by 80-90 degrees.  All Sry mutations in XY females located in HMG box, and alters ability to bend DNA.

Sry transcripts detectable at 10.5 days p.c. in mouse gonad, and differentiation of Sertoli cells into testes cords first detectable at 11.5-12.5 days p.c. But because of limits of detection, transcription may occur earlier, and has been reported in preimplantation mouse embryos.

Other genes

MIS (Mullerian inhibiting substance), also known as AMH (anti-Mullerian hormone) may be downstream target of Sry.

WT1 (Wilm’s tumor gene):  zinc-finger transcription factor, mutations associated with childhood kidney cancer.  Some mutations in WT1 (Denys-Drash syndrome) causes XY sex-reversal, with disordered gonadal histology, persistent Mullerian derivatives, and feminization of external genitalia.  WT1 expression primarily in common mesodermal precursor of kidney and gonad, and detectable at 9 days p.c. in mice.  Mouse with homozygous WT1 knockouts fail to form kidneys or gonads from intermediate mesoderm.

SF-1 (steroidogenic factor), regulator of genes for enzymes needed for steroid biosynthesis.  SF-1 knockout mice fail to make kidneys or gonads.  SF-1 binding site found upstream of MIS (AMH) gene.

Sox9:  mutations in this gene cause campomelic dysplasia, with severe skeletal malformation and varying degrees of feminization of XY individuals with normal Sry genes.  Encodes protein 60% homologous to Sry in the HMG domain.

DAX1:  nuclear hormone receptor gene;  mutations cause one form of adrenal hyperplasia congenita (AHC).  Gene maps to region where duplications cause XY sex reversal.

Wnt-4 regulates female development in mammals (Vainio et al., 1999).  Wnt-4 mutant males appear normal at birth, but Wnt-4 mutant female mice are masculanized (has Wolffian duct instead of Mullerian duct).  Wnt-4 required in both sexes for initial formation of Mullerian duct, suppresses development of Leydig cells in ovary.  Wnt-4 mutant females activate testosterone synthesis.

Genetics of Sex Determination:  Bibliography

Foster et al. (1992) Evolution of sex-determination and the Y chromosome: SRY-related sequences in marsupials. Nature 359:531-532.

Gill ME, Y-C Hu, Y Lin, DC Page (2011) Licensing of gametogenesis, dependent on RNA binding protein DAZL, as a gateway to sexual differentiation of fetal germ cells. Proc Natl Acad Sci USA 108:7443-7448

Gubbay et al. (1990) A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature 346:245-250.

Haqq et al. (1993) SRY recognizes conserved DNA sites in sex-specific promoters. Proc. Natl. Acad. Sci. USA 90:1097-1101.

Koopman et al. (1989) ZFY gene expression patterns are not compatible with a primary role in mouse sex determination. Nature 342:940-942.

Koopman et al. (1991) Male development of chromosomally female mice transgenic for SRY.  Nature 351:117-121.

Mardon and Page (1989) The sex-determining region of the mouse Y chromosome encodes a protein with a highly acidic domain and 13 zinc fingers. Cell 56:765-770.

Page et al. (1987) The sex-determining region of the human Y chromosome encodes a finger protein. Cell 51:1091-1104.

Page et al. (1990) Additional deletion in sex-determining region of human Y chromosome resolves paradox of X,t(Y;22) female. Nature 346:279-281.

Palmer et al. (1989) Genetic evidence that ZFY is not the testis-determining factor. Nature 342:937-939.

Schneider et al. (1989) ZFX has a gene structure similar to ZFY, the putative human sex determinant, and escapes X inactivation. Cell 57:1247-1258.

Simpson et al. (1987) Separation of the genetic loci for the H-Y antigen and for testis determination on human Y chromosome. Nature 326:876-878.

Sinclair et al. (1990) A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346:240-244.

Vainio, S., M. Heikkila, A. Kispert, N. Chin and A.P. McMahon (1999).  Female development in mammals is regulated by Wnt-4 signalling. Nature 397:405-409.

Zwingman et al. (1993) Transcription of the sex-determining region genes Sry and Zfy in the mouse preimplantation embryo. Proc. Natl. Acad. Sci. USA 90:814-817.

3 Responses to Mammalian Sex Determination

  1. Jung Choi says:

    Although international sporting organizations have largely ceased genetic testing for gender, what they replaced it with may be no better:

  2. shamshad says:

    Sir I have many question about the genetics of human I am talking about the sex ratio of male and female in human being. I genetic’s books I will the human being has 46 chromosomes and 23 pairs in these 23 pairs 22 are not involved in sex determination. Only the last one 23rd pair involve in sex determination. Male has XY pair and female has XX pair. These chromosomes separated before after the meosis. Sperm contain X and Y chromosomes and the egg contain X chromosomes only. X and Y chromosome containing sperms are equal in number.
    These all things I read from the books because I have lot of interest in genetics but my question are these
    1: if the fertilization of egg by the sperm is chance then why in older era or 70 to 80s the count of male is higher than the female?
    I was selected 20 houses from my village it is very backward and poor and 0% chances of ultrasound before baby birth or killing of girl because the nurse who does the cases of delivery tell me that she said in my practicing life of 35 year no one case comes when any one mother wants to kill her daughter. So these 20 houses has only 7 girls and 36 boys or male keep in mind these are the one generation before me data.
    2: Diet of male and female before and after the marriage.
    If the male diet is mostly depends on the natural resources and he is stronger than the female why it’s happen the female give the birth to male young one and vice versa. I will also study lot of those families which have more boys and lot of those families hawing more girls.
    3: stress or tension on the male and female after marriage.
    Why it happens if the female is in stress and weaker than the male and the male is strong and don’t care about the tensions why in this case the female in more than 90% chances gives the birth of male young one. And vice versa
    4: why the population of male in villages which are apart from the cities and whose population mostly depends on the natural food resources is higher than the females.
    Why the population of male in most of the villages is higher than the cities in cities most of the families have on average 4 girls and only one boy but in case of villages the case is totally opposite villages has more male population than the female.
    5: condition of male and female before and after the marriage.
    Why in most cases if the female is dominant of male and the male is recessive then the 1st young one is male if she remain dominant on male then she has more female child but if the female after marriage become recessive due to certain reasons then 50% chances has to give birth male to young one.
    6:- environmental conditions
    I in older eras when environmental conditions are harsh and only strong persons can survive in these conditions so males are the best survivors of these conditions. So females give birth to only male baby. So the number of males is so much high in these conditions. But mostly people think that the killing of women or baby girls is so much high just like in Arab just before Islam.
    But I give you several hundred examples of those villages where ultrasound and killing of baby girls is zero. But these villages have so much high number of boy. I am give you several hindered examples of those persons who are drunker and take drugs and they have healthy wives so they have baby girls. I have several examples of those people hawing weak and sick wives and strong and healthy husbands have baby boys.
    Please tell me what answer of these questions is.

    if the human sex determination is depends on the by chance method of sperm fertilization if the sperm contain X chromosome then girl birth is takes place. But in case of Y chromosome male is produced. but i don’t think so because if the process is not depends on the other things and fertilization is by chance process then why in older era the count of males are so high. i have several cases in which strong points are present when the food or diet, stress, environmental conditions, conditions of male and female before and after marriage.
    i don’t think that these things are directly involved in sex determination but these things create environment to fertilize what chromosome to the egg.

    i give you an example we are 5 brothers 2 brothers are poor and live in village and totally depends on the natural resources they wheat bread with milk and grow on vegetables both are married both have 6 boy and only 3 girls.
    But my one brother live in city and his wife is strong and dominant she has all girls and no one is boy.
    Please give me the ans of these questions.
    My English is not so good please ignoring my mistakes of grammar and spell thanks.

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