Biol 4355 - Genética Humana Capítulo 6 – Sobre el Sexo UPR – Aguadilla JA Cardé , PhD

1. Biol 4355 - Genética Humana Capítulo6 – Sobre el Sexo UPR – Aguadilla JA Cardé, PhD

2. Objectives • To describe the factors that contribute to maleness of femaleness • To distinguish between Y and X linkage • To discuss the inheritance pattern of a trait that appears in only one sex • To explain X inactivation: epigenetic and effects on phenotype • To explain the chemical basis of silencing the genetic contribution of a parent • To review examples of imprinting

3. Our Sexual Selves • Maleness or femaleness is determined at conception (which chromosome?) • Another level of sexual identity comes from the control that hormones exert on development • Finally, both psychological and sociological components influence sexual feelings

4. X and Y Chromosomes X chromosome - Contains > 1,500 genes - Larger than the Y chromosome - Acts as a homolog to Y in males Y chromosome - Contains 231 genes - Many DNA segments are palindromes and may destabilize DNA Figure 6.1

5. Sexual Development During the fifth week of prenatal development, all embryos develop two sets of: - Unspecialized (indifferent) gonads - Reproductive ducts – Müllerian (female-specific) and Wolffian (male-specific) An embryo develops as a male or female based on the absence or presence of the Y chromosome - Specifically the SRY gene (sex-determining region of the Y chromosome) (Wnt4, others)

6. Sex Chromosomes Determine Gender Human males are the heterogametic sex with different sex chromosomes, (XY) Human females are the homogametic sex (XX) In other species sex can be determined in many ways - For example, in birds and snakes, males are homogametic (ZZ), while females are heterogametic (ZW)

7. Anatomy of the Y Chromosome Pseudoautosomal regions (PAR1 and PAR2) - 5% of the chromosome - Contains genes shared with X chromosome Male specific region (MSY) - 95% of the chromosome - Contains majority of genes including SRY and AZF (needed for sperm production) Gen o genes paramasculinidad? Figure 6.2

8. SRY Gene Encodes a transcription factor protein Controls the expression of other genes Stimulates male development Developing testes secrete anti-Mullerian hormone and destroy female structures Testosterone and dihydrotesterone (DHT) are secreted and stimulate male structures 46XX males vs 46 XY females = SRY

9. Abnormalities in Sexual Development Pseudohermaphroditism = Presence of male and female structures but at different stages of life - Androgen insensitivity syndrome = Lack of androgen receptors - XY but female phenotype - 5-alpha reductase deficiency = Absence of DHT - males with SRY+ and testes but female pheno - 12 y/o transformation - Congenital adrenal hyperplasia = High levels of androgens - PSD males (3y/o), male 2ndry charac in fem

10. Figure 6.3 Androgen insensivity syndrome Figure 6.4

11. Homosexuality Seen in all cultures for thousands of years documented in 500 animal species Evidence suggests a complex input from both genes and the environment Phenotype and genotype consistent Atraction towards the same sex Studies of identical and fraternal twins Identifying possible markers in X, presents among pair of homosexuals more often

12. Sexual Identity Components Table 6.1

13. Sex Ratios Mendel: predicts that equals number of male and females - social, environment can select for one gender The proportion of males to females in a human population should be 1:1 Calculated by # of males / # of females multiplied by 1,000 Primary sex ratio – At conception (EU, 1050) Secondary sex ratio – At birth (China, India) Tertiary sex ratio – At maturity, (EU 65+ , 720) Sex ratios can change markedly with age - medical conditions or environment affects sexes differentially

14. Y-linked Traits Genes on the Y chromosome Y-linked traits are very rare Transmitted from male to male No affected females Currently, identified Y-linked traits involve infertility and BTW, obviously not transmitted X – has more genes than Y, more mutants with consequences Account for ~10% of Mendelian diseases (one gene) Genes in X have different pattern of expression in each sex In females are passed as autosomal (two copies) In males are passed as dominant (one copy)

15. Sex Determination in Humans Figure 6.4 Figure 6.6

16. X-linked Traits Possible genotypes X+X+ Homozyogus wild-type female X+XmHeterozygous female carrier XmXmHomozygous mutant female X+Y  Hemizygous wild-type male XmY Hemizygous mutant male

17. X-linked Recessive Inheritance

18. X-linked Recessive Traits Examples: - Ichthyosis = Deficiency of an enzyme that removes cholesterol from skin - Color-blindness = Inability to see red and green colors - Hemophilia B = Disorder of blood-clotting

19. Ichthyosis= Deficiency of an enzyme that removes cholesterol from skin • Middle-aged man • 1 y/o grand-son skin resembles his. • Cholesterol removed by an enzyme, blocked in this condition • Daughter produced half the enzyme ammount Figure 6.7 Figure 6.5

20. Figure 6.6 Figure 6.8

21. X-linked Dominant Inheritance

22. X-linked Dominant Traits • Rare traits • Expression differ between sexes (severity) • Females : swirls of skin, melanin, puz filled vesicles, warts, spots) • Males : die before born • Carriers have 25% of misscarriages • Incontinentiapigmenti Figure 6.7

23. X-linked Dominant Traits • Congenital generalized hypertrichosis • Many extra follicules • More dense and abundant hair upper body • Females patchy and milder (hormones and another X) • Note: no sons inherited the condition Figure 6.8

24. Solving Problems: X linked Steps to follow: 1) Look at the inheritance pattern 2) Draw a pedigree 3) List genotypes and phenotypes and their probabilities 4) Assign genotypes and phenotypes 5) Determine how alleles separate into gametes 6) Use Punnett square to determine ratios 7) Repeat for next generation

25. Kallman Syndrome - Assigned Causes very poor or absent sense of smell and small gonads. 1) Its X linked, recessive 2) Tanisha does not have it, but her brother Jamal an her maternal cousin Malcolm (her mother’s sisters’ child) have it 3) Tanisha’s and Malcolm’s parents are unaffected 4) Tanisha’s husband Sams is unaffected 5) Tanisha and Sam want to know the risk that a son would inherit the condition. Sam has no afffected relatives.

26. Sex-Limited Traits Traits that affect a structure or function of a body part occurring only in one sex The gene may be autosomal or X-linked Examples: - Beard growth – women do not grow it, but can pass the mutation to sons - Milk production – males not make milk but can pass the trait - Preeclampsia in pregnancy – male genes affect placenta, that’s affect women bp(Assigned)

27. Sex-Influenced Traits Traits in which the phenotype expressed by a heterozygote is influenced by sex Allele is dominant in one sex but recessive in the other Example: - Pattern baldness in humans - A heterozygous male is bald, but a heterozygous female is not - trait may be affected by hormonal differences - Gene for baldness have to alleles (Hairy (h) and bald (H) - Males: H dominant over h, females inverse - males Hh=?; females Hh = ? Females HH ?

28. X Inactivation Females have two alleles for X chromosome genes but males have only one In mammals, X inactivation balances this inequality and one X chromosome is randomly inactivated in each cell The inactivated X chromosome is called a Barr body, the women becomes a mosaic for expression of most genes on the X

29. X Inactivation X inactivation occurs early in prenatal development It is an example of an epigenetic change - An inherited change that does not alter the DNA base sequence The XIST gene encodes an RNA that binds to and inactivates the X chromosome

30. Figure 6.9 Figure 6.12

31. X Inactivation • A female that expresses the phenotype corresponding to an X-linked gene is a manifesting heterozygote • In homozygous X linked genotypes, has no effect • X inactivation is obvious in calico cats (XB/XY) • Incontinentiapigmenti • Hunter syndrome/ Fabry dis • Lesch-Nyhan Syndrome (Asig) • An allele of and X gene that stimulate cell division? • Two X gene proteins interacts Figure 6.10

32. Genomic Imprinting The phenotype of an individual differs depending on the gene’s parental origin Genes are imprinted by an epigenetic event: DNA methylation - Methyl (CH3) groups bind to DNA and suppress gene expression in a pattern determined by the individual’s sex Imprinting pattern is passed from cell to cell in mitosis but not from individual to individual in meiosis

33. Imprints are erased during meiosis - Then reinstituted according to the sex of the individual During mitosis replication pattern is passed exactly or imprinted During meiosis the CH3 pattern is removend and reset, according to cygote sex. Womens can have son and males can have daughter without passing their specific parental imprints Figure 6.11

34. Importance of Genomic Imprinting Function of imprinting isn’t well understood, but it may play a role in development – brains genes Research suggests that it takes two opposite sex parents to produce a healthy embryo - Male genome controls placenta- (ovum with 2 male pronuclei) development but tiny and stopped - Female genome controls embryo development - (ovum with 2 females pronuclei) – developed but aberrant placenta Genomic imprinting may also explain incomplete penetrance (one imprinted gene can silence de dominant mutant alllele.

35. Imprinting and Human Disease Two distinct syndromes result from a small deletion in chromosome 15 - Prader-Willi syndrome - Deletion inherited from father; genes not normally imprinted, are missing, only mothers expressed - Eating disorder – obesity, compulsive - Angelmansyndrome - - Deletion inherited from mother -autism, lack of muscle coordination The two syndromes may also result from uniparentaldisomy

36. Imprinting and Human Disease Deletion on chromosome 15 reveals imprinting Figure 6.14