1. Capítulo 6 – Sobre el Sexo
Biol Genética Humana
Capítulo 6 – 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
El sexo afecta nuestras vidas en multiples formas:
el cromosoma q nos toque en la concepción establece el programa de desarrollo para masculinidad o femeneidad
Expresion genética diferencial, antes y después del nacimiento, influencia grandemente como ese programa se despliegue

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
El cromosoma Y incluye
Dos regiones autosomales
una región male-specific que no se recombina
genes en Y pueden se correspondientes a los de X, similares a estos o únicos
arreglo palindromico de DNA en Y puede aportar a la inestabilidad de genes de Y
Figure 6.1 4

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)
Generos se hacen aparentes en la 9na semana del desarroll
En la 5ta todos los embriones tienen: Gonadas no diferenciadas y ductos reproductivos
Si los mullerian se desarrollan female
Si wolfian se desarrollan males
Se escoge en la 6ta semana
Si esta la Y con el SRY se bloquea mullerian y PLT se desarrolla Wolf
Si no esta SRY activo sigue Mulleria
Wnt4 – este gen mutado causa una hembra con altos niveles de Testosterona sin fenotipo femenino
Asi q no solo es que SRY no este, sino q si Muller sigue su ruta, Wnt4 tiene q ayudar … 5

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)
El varon en humano es heterogametico sexualmente hablando y la hembra es un sexo homogametico 6

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 para masculinidad?
El cromosoma Y incluye
Dos regiones autosomales – sufre recomb con regiones del X, genes de ambos sexos
para inmunidad, division celular, receptores, hormonas, metabolismo de ATP etc
Una región male-specific que no se recombina
genes en Y pueden se correspondientes a los de X, similares a estos o únicos
los unicos tienen arreglo palindromico de DNA en Y puede aportar a la inestabilidad de genes de Y para fertilidad
MSY codifica para muchos segmentos de proteinas que se recombinan de muchas formas
NO es facil cuantificar cuantas proteinas hay en este Cromosoma
Figure 6.2 7

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
Junto a muchos otros genes importante para fertilidad
En la busqueda para genes para sexo o masculinidad paso mucho tiempo
46XX males vs 46 XY females = SRY
XX - tienen un fragmento de 1% del Y
XY – les falta 1% del Y
El mismo 1% = SRY 8

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
Desarrolloo prenatal es sumamente complejo
Mutaciones pueden afectar el desarrollo masculino interviniendo en muchos puntos
Puede resultar en un 46 XY con fenotipo femenino!!!!
SRY on destruye female structures
Activa ruta para testosterona y DHT
Androgen insensivity sindrome faltan receptores para testos sera XY pero se vera female Mutacion en Gen en X
Hemafroditas – estructras e ambos sexos termino antiguo
Intersex-internas y externas structures no son consistentes
Pseudo hemarfro – ambas estructuras male y female en distintas etapas de crecimiento
5 alfa reductasa deficiency – autosomal recesivo
Males con SRY + y testes but externamente es female,
Ser desarroola por dentro male pero por fuera hasta pubertad
Ahi las suprarenales producen testosterona desarrollan carac masculinas
No menses, clit se convierte en pene
Fertiles
Females XX con la misma condicion son females/females
CAH –recesiva autosomal
21 hydroxylsa deficiency
Se acumulan Test y DHT
Puberta precoz en males (3y/o)
y carac 2rias masc en females – nace con clit inflamados
Female internas pero voz vellos e infertilidad, no mens
Ya el diagnostico 9

10. Figure 6.4 Figure 6.3 Androgen insensivity
syndrome
Desarrolloo prenatal es sumamente complejo
Mutaciones pueden afectar el desarrollo masculino interviniendo en muchos puntos
Puede resultar en un 46 XY con fenotipo femenino!!!!
SRY on destruye female structures
Activa ruta para testosterona y DHT
Androgen insensivity sindrome faltan receptores para testos sera XY pero se vera female Mutacion en Gen en X
Hemafroditas – estructras e ambos sexos termino antiguo
Intersex-internas y externas structures no son consistentes
Pseudo hemarfro – ambas estructuras male y female en distintas etapas de crecimiento
5 alfa reductasa deficiency – autosomal recesivo
Males con SRY + y testes but externamente es female,
Ser desarroola por dentro male pero por fuera hasta pubertad
Ahi las suprarenales producen testosterona desarrollan carac masculinas
No menses, clit se convierte en pene
Fertiles
Females XX con la misma condicion son females/females
CAH –recesiva autosomal
21 hydroxylsa deficiency
Se acumulan Test y DHT
Puberta precoz en males (3y/o)
y carac 2rias masc en females – nace con clit inflamados
Female internas pero voz vellos e infertilidad, no mens
Ya el diagnostico
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
Nadie sabe en realidad porq nos sentimos pertenecer a un genero o atraido a un genero o no?
Se sabe que es intenso
Homo sexualidad genotipo y fenotipo es cosistente, atraccion al mismo sexo
Es influenciada por genetica y por ambiente
Gemelos identicos mas tendencia a los dos serlo q los fraternos
Marcadores geneticos en X mas parecidos entre hnos homos q entre otros hermanos, estudios no confirmados
Heredabilidad del rasgo 35% en hombres vs 18% en hembras PLT hay mchosgenes y ambiente 11

12. Sexual Identity Components
Resumen de los componentes de la identidad sexual
Sexualidad y homosexuallidad reflejan el imput de varios genes y de factores ambiental
Y varios origenes
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
Sex Ratio : numero de machos dividido entre el numero de hembras multiplicado por 1000 para cada edad.
Interferencia con los embarazos puede desviar los ratios
1050 en eu los ultimos 60 anios
Espermatozoide con Y es mas liviano que el X PLT nada mas facil llega mas rapido ?
Con la edad: se afectan las proporciones por condiciones medicas o por conductas como guerras y conductas de alto riesgo 13

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)
Y linked son raros porque hay pocos genes en Y y porqu tienen su contraparte en
Males are hemizygous for X linked traits 14

15. Sex Determination in Humans
Figure 6.4
Un ovulo trae una sola X. En sperm trae o una X o una Y.
Si un esperma con Y con el SRY funcional llega al ovulo XY male
Si es una X con otra X female
A male inherits his Y from father and X from mother
Female inherits X for each parent
IF mother is heterozygous her son or daughter hast 50% chance of inheriting
There is no male to male transmission of X linked traits
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
Rasgos Ligados a X se expresan en females si son homocigotas
Muchas veces se pasa un rasgo recesivo de una madre no afectada a un hijo afectado
Ver tabla 6 16

17. X-linked Recessive Inheritance
Summarizes the transmission of an X linked recessive trait
Si no son letales, hombre sobrevive y deja progenie 17

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
Rasgos donde el padre sobrevive para dejar progenie.. Rasgo no es letal ni afecta fertilidad
Ichthyosis – Enzima para remover colesterol – Abuelo y nieto la tienen
Daltonismo – 8% hombres europeos, 4% hombres de africa pero 0.4% de mujeres
Hemophilia B – Christmas disease: (Stephen Chtistmas young first diagnoses 1952 18

19. 1 y/o grand-son skin resembles his.
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
Ichthyosis = Deficiency of an enzyme that removes cholesterol from skin
Middle-aged man with rough, brown, scaly skin
Realize the condition is genetic when his 1 y/o grand-son skin resembles his.
Cholesterol removed by an enzyme, blocked in this condition, skin upper layer cant peel normally
Daughter produced half the enzyme ammount
Figure 6.7
Figure 6.5

20. Figure 6.6
Hemophilia – Christmas Diseases by Steven Christmas 1952
Note the combination of Punnet Square and Pedigrees diagrama to follow the condition
Superscritos denotes dominant and recessive alleles in Y or X
Queens Victoria origins the allel, mutated or inherited
She passed it to her daughters on a mildly affected son
Transmission is consistent with X linked, recessive
Figure 6.8

21. X-linked Dominant Inheritance21

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
Incontinentia pigmenti
Gene NEMO causes IP
Activates immune response, apoptosis on the ectoderm derived structures
Skin, nAILS, eyes, hair, brain
Figure 6.7 22

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
Many extra hair follicules
More dense and abundant upper body hair
IN females is patchy and milder because the other X and the hormones
Hijos varones no reciben la X del padre.. No tienen nada
Figure 6.8 23

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 24

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.
XkX Tan Jamal XkY Malcom XkY
Parents XkX y XY XkX y XY
Sams XY x XkX
½ de que sea XkY 25

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) 26

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 ? 27

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 28

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
Some rare females lost a small part of the X chromosome, identified as the Chromosom inactivation center
Genes in the pseudoautosoma region and some other escape the inactivation
XIST controls the inactivacion binding in an specific site of the inactivated X and maintains it silenced 29

30. Once and X is inactivated in one cell (8 cells embryo); all descendants will have the same X inactivated
This will create patches of tissue that differ in their expression of the X linked genes
Each cell will have only one X active, , equivalent to males in terms on X gene expression
At celular level is observed because the X inactivated stain darker and faster than the active
Females has one Barr body, Males dont
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)
Incontinentia pigmenti
Hunter syndrome/ Fabry dis
Lesch-Nyhan Syndrome (Asig)
An allele of and X gene that stimulate cell division?
Two X gene proteins interacts
In manifesting heterozygotes the X inactivation has no effect in health, if there is enough normal alele expressing cells, the inactivation has no effect
Incontinentia pigmentis: swirl of skin colors due to some x with mutant melanin production gene (pale zones) and some normal X for melanin production (normal color)
Calico cats: XB brown dominant, XY yellow recesive
Female heterocigote will have patches brown and yellow depending which X is inactivated in each area
Human skin cells disperse in development, in cats not
So males never calico unless having and extra X,
Hunter – lyzosimes storage disorder: mucopolisacaridosis II
Deficiencia en enzima q remueve debris celular en el lizosoma
XXh – no tienen sintomas porq algnas celulas producen la enzima
XhY – sordos, enanos, problmas cardiacos etc
Fabry – no producen la enzima alfa galactosidasa A
XXf – algunas celulas affectadas otra no mild symptoms
XfY – fallo renal….
Calicos always females (XX)
Figure 6.10 31

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
In mammals the parental origins of the gene affects the phenotype
Metilation used to regulate gene expresion, preventing being accesed and expressed
Epigenetic: change the meaning of the information in the gene without altering the sequence
Passd 32

33. Imprints are erased during meiosis
Figure 6.11
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 33

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. 34

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
- Angelman syndrome -
- Deletion inherited from mother
-autism, lack of muscle coordination
The two syndromes may also result from uniparental disomy
Mas de 159 imprinted genes
60 of them health issues related when abnormally expressed
Effects observed when an individual has one copy of a normally imprinted allele and the other copy is inactivated o deleted
Imprinting means inactivation 35

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