This document discusses human genetics and sexual development. It covers several topics: 1. Genetic, gonadal, and phenotypic sex are determined by sex chromosomes, presence of SRY gene on Y chromosome, and hormone levels. 2. Sex is genetically determined by X and Y chromosomes. The Y chromosome contains the SRY gene which initiates testis formation. 3. Hormones like testosterone and MIS then direct the development of either male or female external genitalia and the regression of duct systems not needed for that sex.

1. HUMAN GENETICS
BMD 404
First Semester (2016/2017)
By
Desmond Omane Acheampong

2.  Sexual Development
 Genetic Sex
 Genetic male
 Genetic female
 Gonadal Sex
 Testis
 Ovary
 Phenotypic sex
 Male external genitalia
 Female external genitalia

3.  Genetically determined Sex:
Sex Chromosomes
In humans they are called X & Y Chromosomes
Sex determination primarily depends on presence or
absence of Y chromosome
Y chromosome is necessary for the formation of
testis
Testis producing gene product – SRY (Sex-
determining Region Y protein)

5. • SRY
DNA binding regulatory protein
It binds the DNA and act as a transcription
factor that initiates transcription of a cascade
of genes necessary for testicular formation
The gene for SRY is located at tip of the short
arm of the Y chromosome

6.  Gonadal Development and Sex
Determination
On either side of the embryo, a
primitive/unspecialized gonads arises from the
genital ridge
Develops as Cortex & Medulla
Initially ambi-sexual (up to 6 weeks)

7. In genetic males:
Medulla develops into testis (7 – 8 weeks)
Cortex regresses
Leydig cells (found adjacent to the seminiferous
tubules in the testicle) & Sertoli cells (part of a
seminiferous tubule and helps in the process of
spermatogenesis) appear
Testosterone & MIS (Mullerian-inhibiting
substance) are secreted by Leydig & Sertoli cells
respectively

8. In genetic females
Cortex develops into Ovary
Medulla regresses

9. • Embryo
Embryo with functional testis (Male):
Leydig cells secrete Testosterone to fosters the
development of Wolffian duct system
Sertoli cells secrete MIS to inhibits development of
Mullerian duct system
Wolffian duct system develops into Epididymis /
Vas deferens / Seminal vessicles

10. Embryos with functional Ovary (females):
No testosterone so Wolffian duct system regresses
No MIS so allows development of Mullerian duct
system
Mullerian duct system develops into Fallopian tubes
/ Uterus / Cervix / Upper vagina

12. Until 8 weeks in embryonic life, the external
genitalia are bi-potential
 Development of External genitalia
• In the presence of testosterone (male):
Testosterone is converted to DHT
(dihydrotestosterone) by 5-alpha reductase
DHT promotes the development of bi-potential
external genitalia to become Male External Genitalia
Enlargement of genital tubercle – Penis

13. Fusion of urethral fold over uro-genital sinus –
Penile urethra
Fusion of labio-scrotal swelling – Scrotum
• In females:
No Testosterone
No DHT
Therefore the bi-potential external genitalia
differentiates in to female external genitalia
Genital tubercle remains – Clitoris

14. Non fusion of uro genital sinus – Lower vagina &
urethra (vestibule)
Non fusion of urethral folds – Labia minora
Non fusion of labio scrotal swelling – Labia
majora

16.  Hermaphroditism
• Chromosomal abnormalities
• Hormonal abnormalities
• Chromosomal Abnormalities:
non-disjunction of sex chromosomes during the first
meiotic division usually leads to Non disjunction
during second meiotic division – more complex
abnormalities
Non disjunction during mitotic division after
fertilization – Mosaicism – True Hermaphrodite –
Individual with ovaries & testis

17. • Hormonal abnormalities:
Female pseudo-hermaphroditism
Exposure to exogenous androgens during
development (8 – 13 weeks)
Congenital Adrenal Hyperplasia
o Female type gonads and internal genitalia but male
external genitalia

18. Male pseudo-hermaphroditism
Defective testicular development
Androgen insensitivity syndrome
o 5-alpha reductase deficient
o Androgen receptor mutation
o 17-alpha hydroxylase deficiency

19. Traits Inherited on Sex Chromosomes
Genes on the Y chromosome are said to be Y-linked,
and those on the X chromosomes are X-linked.
Y – linked traits are rare, because it contains few genes
which have their counterparts on the X –
chromosomes.
The Y – linked traits are pass from male to male only
The only clearly identified traits associated Y
chromosome is infertility.

20. In female, X – linked traits are passed just like
autosomal traits. Two copies are required for
expression of a recessive allele and one for
dominant allele.
In a male a single copy of an X – linked allele
causes expression of the trait
 Male is considered hemizygous for X – linked
traits

21.  X – linked recessive inheritance
An X – linked recessive trait is expressed in females
if the causative allele is present in two copies.
Usually, an X – linked trait passes from an
unaffected heterozygous mother to an affected son
A man may be healthy enough to transmit it to
offspring, if an X – linked condition is not lethal.

22. • Real case:
A man who had a condition called ichthyosis
characterized with rough, brown, scaly skin, did not
realize his condition was inherited until his daughter
had a son.
By age one the boy’s skin resembled his
grandfather’s

23. An enzyme deficiency blocks removal of
cholesterol from skin cells. As a result, the upper
skin layer cannot peel off, causing a brown, scaly
appearance.
A test of the daughter’s skin cells revealed that she
produces half the normal amount of the enzyme,
indicating that she is a carrier.

24. Another X – linked recessive trait that is not lethal
and therefore does not prevent a man to have
children is colour blindness.
8% of males of European ancestry, 4% of males of
African descent as against 0.4% of females of both
groups have colour blindness.
There are three types of cone cells, defined by the
presence of any of three types of
photopigmentation.

25. An object appears coloured because it reflects
certain wavelengths of light, and each cone type
captures a particular range of wavelengths with its
photopigment.
Each photopigment has a vitamin A – derived
portion called retinal and a protein portion called
an opsin.
The opsin is present because colour vision is
controlled by genes

26. The three types of opsin correspond to short, middle
and long wavelengths of light.
Mutation in opsin genes cause three different types
of colour blindness.
A gene on chromosome 7 encodes short
wavelength opsin, and mutation results in rare
autosomal blue form of colour blindness.

27. Deuteranopia (green colour blindness) means the
eyes lack middle – wavelength opsin, which is
encoded by genes on the X chromosome
Protanopia (red colour blindness) means the eyes
lack long – wavelength opsin, which is encoded by
genes on the X chromosome

29.  X – Linked dominant inheritance
Dominant X – linked conditions and traits are rare.
A female with dominant X – linked allele has the
associated trait or illness.
A male who has the allele is usually more severely
affected
Example of an X – linked dominant condition is
incontinentia pigmenti (IP), an inborn error that
Archibald Garrod described in 1906.

30. The name is a reflection of the major sign in
affected females, that is swirls of skin pigment that
arise when melanin penetrates the deeper skin
layers.

31. A newly born girl with IP has yellow, pus – filled
vesicles on her limbs that come and go over the first
few weeks.
The lesions then become warty and eventually give
way to brown splotches that may remain for life,
although they fade with time.
It could be associated with other symptoms such as
patches of hair loss, visual problems, peg –
shaped or underdeveloped teeth and seizures,
mental retardation, paralysis, and developmental
delay occur.

32. Males who inherit the condition are so severely
affected that they do not survive to be born. This
explains why about 25% of women with the
condition miscarry.
The gene that causes IP is called NEMO which
encodes a transcription factor that activates genes
that carry out the immune response and apoptosis in
tissues that are derived from ectoderm, such as skin,
hair, nails, eyes and the brain.

34. X Inactivation
Unlike males, females have two alleles for every
gene on the X chromosome. Therefore X
inactivation balances this inequality among the
sexes.
Early in the development of the female embryo,
most of the genes on one X chromosome in each
cell are inactivated. The inactivation is random.
As such, some cells express the genes on X
chromosome from the mother whereas others
express genes on X chromosome from the father.

35. There is a specific region on the X chromosome
that shuts off some genes on X chromosome. This
region is called X inactivation centre.
However, some few genes on the chromosome still
remain active. Eg genes in the pseudoautosomal
regions (PARs) and some others escape inactivaton.

36. The moment X chromosome is inactivated in one
cell, all the daughter cells have the same X
chromosome inactivated.
In view of the fact that the inactivation occurs early
in development, the adult female has patches of
tissue that differ in their expression of X – linked
genes.
Because each cell in her body has only one active X
chromosome, she is chromosomally equivalent to
the male.

37. The gene that controls X inactivation is called
XIST.
XIST encodes an RNA that binds to a specific site on
the inactivated X chromosome.
The region between the point where the RNA binds
to the chromosome and the tip of the chromosome is
inactivated.

38. X inactivation can alter the gene expression, but not
genetype. This is because, the inactivation is not
permanent, it is reversed in germline cells that
become oocytes.
 This implies that a fertilized ovum does not have an
inactivated X chromosome.

39. It is very easy to observe X inactivation at the
cellular level because the inactivated chromosome
absorbs stain much faster than the active X
chromosome.
Inactivated DNA has the methyl group (CH3) that
prevent it from being transcribed into RNA and also
play role in the absorption of the stain.

40. Sex – Limited Traits
Sex – limited traits affect the structure or function of
the body, present, in only males or only females.
Genes responsible for these sex – limited traits may be
X – linked or autosomal.
Eg1, Beard growth and breast size are sex – limited
traits. Women don’t grow beard because they don’t
produce the hormones required for facial hair growth.
 Eg 2, Preeclampsia is a sudden increase in blood
pressure in pregnant women as the birth time nears.

41. • It tend to occur in women whose mothers were
affected. However it has also been proven that if a
man’s first wife had the condition, his second wife
has double the risk of been affected
• Again, in another study, it became evident that
women whose mother – in law had preeclampsia
when pregnant with the woman’s husband had about
twice the risk of developing the condition.

42. Sex Influenced Traits
In this situation, an allele is dominant in one sex
but recessive in the other. This may be X – linked or
autosomal.
This different expression pattern can be caused by
hormonal differences between the sexes.
Eg, an autosomal gene for hair growth pattern has
two allele, one that produces hair all over head and
another that causes baldness.

43. The baldness allele is dominant in males but
recessive in females.
A heterozygous male is bald but female counterpart
is not.
A bald woman is homozygous recessive.

44. Homosexuality and Genetics
 In Homosexuality, affected individuals are physically
attracted toward members of the same sex.
 This sexual orientation has been observed for thousand of
years.
 Earlier investigation points to the fact that young children
with homosexuality tendencies experience it well before they
know of its existence.
 Studies with twins have suggested genetic influence:
Eg, a study in 1991 found that identical twins are more likely
to be both homosexual than both members of fratenal same –
sex twin pairs.

45. 52% of identical twins pairs in which one was
homosexual, both brothers were homosexual but
only 22% of fratenal twin pairs were homosexuals
.
In 1993, another study traced the inheritance of five
genetic markers on the X chromosome in 40 pairs of
homosexual brothers.
Although these DNA sequences were highly
variable in the general population, they were
identical in 33 of the sibling pairs.
The interpretation was that genes causing male to be
homosexual reside on the X chromosome.

46. Unfortunately, this study never identified the
specific gene responsible for homosexuality.
The findings of this study is still controversial (Dean
Hamer).
There was another study which seemed to confirm
the findings of Dean Hamer.
 In this study, siblings were considered. Two
homosexual brothers had another brother who was
heterosexual .

47. The heterosexual brother did not share the X
chromosome markers
Several researchers have refuted Hamer’s findings,
citing that gene controlling homosexual need not
reside on a sex chromosome, where Hamer devoted
all his time.
As a result ongoing studies are searching among the
autosomes for such genes.

48. Scientists altered male fly embryos so that the adult
insects expressed the white gene in every cell of the
insect.
This genetically manipulated male exhibited what
looks like a mating behaviour with each other.
The ability to genetically induce homosexual
behaviour suggest possible genetic control.
In the quest to still understand the genetics of
homosexuality, Scientists have genetically
manipulated male fruit flies to display what appears
to be homosexual behaviour.
A mutant gene called white for white eye colour
when expressed in cells of the eye only.

49. The biochemical basis of the phenotype of the white
gene makes sense.
The white gene translate into an enzyme that controls
eye colour. These enzyme enables cells to use the amino
acid tryptophan.
The ability to use tryptophan is a requirement to
manufacture the hormone serotonin.
When all the fly’s cells express the mutant white gene,
instead of just cells of the eye, serotonin level in the
brain drops, which may cause the homosexual
behaviour.

50. Genomic Imprinting: An Epigenetic Modification
Parent-of-origin Effect:
• One of the tenets of Mendelian genetics is that
reciprocal crosses with autosomal loci produce the
same ratio and phenotypes among the offspring.
• Eg, parents who are each homozygous for different
autosomal alleles have only heterozygous offspring
with the same phenotype regardless of the type of
dominance

51. A1A1(female) x A2A2 (male) A1A1 (male) x A2A2 (female)
Genotype: A1A2 A1A2
Phenotype:
If A1 is dominant A1 A1
If A2 is dominant A2 A2
If incomplete A1A2 A1A2
dominance

52. • An indication of a non-Mendelian process is the
consistent lack of phenotypic equivalence from
reciprocal matings.
• This situation may arise when an allele from parent
always determines the phenotype and the other
allele, although present and not mutated is not
expressed.
• In these instances, either the paternal or maternal
allele at a particular locus is functional and the other
allele derived from the mother or father,
respectively, is repressed (silenced).

53. A A1A1(female) x A2A2 (male) A1A1 (male) x A2A2 (female)
Genotypes: A1A2 A1A2
Phenotype: A2 A1
B B1B1 (female) x B2B2 (male) B2B2 (female) x B1B1 (male)
Genotype: B1B2 B1B2
Phenotype: B1 B2

54. • Theoretically, some X-linked loci may also show a
parent-of-origin pattern of inheritance.
C C1C1(female) x C2Y (male) C2C2 (female) x C1Y (male)
Genotype: C1C2 (female) C1Y (male) C1C2 (female) C2Y (male)
Phenotype: C2 Lethal C1 Lathal
D D1D1 (female) x D2Y (male) D2D2 (female) x D1Y (male)
Genotype: D1D2 (female) D1Y (male) D1D2 (female) x D2Y (male)
Phenotype: D1 D1 D2 D2

55. • In each of these four examples of non-Mendelian
inheritance, the activity of particular allele is
predicated on the sex of the parent.
• The process that leads to the expression of an allele
that is inherited from one parent and the inactivation
of its counterpart in the other parent is an epigenetic
phenomenon called genomic imprinting.
• Epigenetic is the study of heritable changes in gene
expression (active versus inactive genes) that does
not involve changes to the underlying DNA
sequence.
• The two salient features of genomic imprinting are
heritability and reversibility.

56. • Heritability signifies the biological transmission of
either an active or an inactive allele from a parent to
an offspring.
• Reversibility denotes the ability of the
transcriptional status of an allele to be wiped clean
during each generation before the establishment of a
new imprint that is determined by the sex of the
parent.
• There about 50 known loci, and possibly as many as
200, where the parent-of-origin specifies whether
an allele is transcribed or inactivated in human
somatic cells.

57. • Generally, the terms ‘‘imprinted gene’’, ‘‘genomic
imprint’’ or ‘‘imprint’’ refer only to the allele that
has been silenced.
• The active allele is assumed to occur by default.

58. Gene Silencing
• Genomic imprinting is a cyclical process that
normally endures for one generation.
• Both imprints from the previous generation are
erased in primordial germ cells and replaced with a
paternal and maternal imprint during
spermatogenesis and oogenesis respectively.
• The imprint of each allele at a locus is usually
maintained through all somatic cell divisions
following fertilization.
• If an active imprinted allele is not transcribed in all
cell types, it is turned on at the appropriate time and
cellular site.

59. • Studies of the molecular differences between pairs
of oppositely imprinted alleles have identified some
gamete-specific processes that contribute to the
regulation of individual alleles.
• DNA methylation has been identified as the
principal means of parent-of-origin allele silencing.
• DNA methylation entails the addition of a methyl
(CH3) group to a cytosine residue in DNA that is
immediately, 5’ to a guanine residue. That is,
cytosine of a CpG dinucleotide is methylated.
• DNA methylation is established and maintained by
DNA methyltransferase.

61. • The extent of DNA methylation is inversely
correlated with gene activity.
• The regions of CpG repeats (CpG islands), that
precede commonly expressed genes (housekeeping
genes) are not methylated.
• However, genes that are transcriptionally inactive
are frequently heavily methylated.
• During early mammalian development, the level of
methylation of genomic DNA undergoes dramatic
changes.
• After the zygote is formed, almost all of the
chromosomal DNA demethylated, and as
development proceeds, both general and gene-
specific DNA methylation is restored.

62. • Despite the well documented relationship between
DNA methylation and repression, some genes
require methylation to be active.
• DNA methylation can affect gene transcription
either directly or indirectly:
A methylated promoter region may block
transcription by preventing the binding of
transcription factors.
The DNA methyl groups may bind a protein that, in
turn binds other proteins that change the
conformation of the chromosome and make the
promoter region inaccessible to transcription.