educational guide

1. Human Genetics
BMD 404
WEEK ONE

2. Transmission Genetics
• Genetic transmission is the transfer of genetic
information from genes to another generation (from
parent to offspring), almost synonymous with
heredity, or from one location in a cell to another.

3. Mendel’s Experiments
• Based on results of his experiments, Mendel
determined:
1. that each parent passed one allele of a particular
gene to their offspring and
2. that alleles could form new combinations during
fertilization, leading to phenotypes in offspring that
were not observed in the parents.

4. • Alleles for some phenotypes are dominant and others
are recessive.
• Keep in mind that dominance and recessiveness are
not intrinsic properties of an allele;
 They are instead, effects that can only be measured in
relation to the effects of other alleles of the same gene.

5. Genetic Inheritance in Humans
• Phenotypes that are passed on to the offspring
according to the inheritance rules described by
Mendel are what we call Mendelian inheritance
patterns.
• Similar patterns of inheritance occur in a wide variety
of organisms, including humans.

6. • We also know that the environment plays a strong
role in determining phenotypes, and
• Some phenotypes can be inherited through
mechanisms other than gene sequence variations
(known as epigenetics).

7. Mendelian patterns in human genetics
There are only a few clear cases of classic Mendelian inheritance
of human traits
1. Human eye colour is a trait that is often described as
a simple Mendelian trait, with brown eye colour
being dominant over green or blue eye colour
• However, recent studies have shown that two key
genes involved in pigmentation of the iris can modify
each other, resulting in multiple shades of brown,
gray and blue

8. Other Examples
1. The consistency of earwax: it can be dry or wet, and
these traits appear to be controlled by two alleles on
a single gene. The allele for wet earwax is dominant
over the allele for dry earwax.
2. The ability to bend back the thumb nearly 90
degrees (known as hitchhiker's thumb)
3. The ability to roll ones tongue into a U-shape, or
whether one's earlobes are attached or free

9. • Some single-gene genetic disorders or mutations,
which can cause debilitating disease and death, also
exhibit patterns of inheritance that follow Mendel's
rules or nearly so.
• Other genetic diseases are somewhat more complex
but still follow basic probability rules.

10. • For example, haemophilia A is influenced by a gene
on the X chromosome.
• Because males only have one X chromosome (other
is Y Chromosome inherited from fathers), they will
express the disease phenotype if they inherit the allele
on the X chromosome from their mothers.

11. • When a certain gene is known to cause a disease, we
refer to it as a single gene disorder or a Mendelian
disorder.
• Single gene disorders are caused by DNA changes in
one particular gene, and often have predictable
inheritance patterns.
– For example, cystic fibrosis, sickle cell disease, Fragile X
syndrome, muscular dystrophy, or Huntington’s disease.
Single Gene Inheritance?

12. • Over 10,000 human disorders are caused by a change
in a single gene, known as a mutation,.
• The mutated version of the gene responsible for the
disorder is known as a mutant, or disease allele.
• Individually, single gene disorders are very rare, but
as a whole, they affect about one per cent of the
population.

13. • Since only a single gene is involved, these disorders
can be easily tracked through families and the risk of
them occurring in later generations can be predicted.
• Single gene disorders can be divided into different
categories: dominant, recessive and X-linked.

14. Dominant diseases
• Dominant diseases are those gene disorders that occur
in the heterozygous state – when an individual has
one mutant copy of the relevant gene and one healthy
copy.
• The effects of the mutant version of the gene (allele)
override the effects of the healthy version of the gene.
So, the mutant allele causes disease symptoms even
though a healthy allele is present.

15. • Dominant disorders tend to crop up in every
generation of an affected family because everyone
carrying a dominant mutant allele shows the
symptoms of the disease.
• Dominant disorders spread vertically down family
trees, from parent to child.

16. • In rare cases when an individual has two copies of the
mutant gene (i.e. homozygous) the disorder
symptoms are generally more severe.
• An example of a dominant single gene disorder is
Huntington’s disease, which is a disease of the
nervous system.

17. A pedigree diagram showing the
inheritance pattern of a dominant disease
(What is a pedigree diagram? )

18. Recessive Diseases
• Recessive diseases are single gene disorders that only
occur in the homozygous state - when an individual
carries two mutant versions (alleles) of the relevant gene.
• The effects of the healthy allele can compensate for the
effects of the mutant allele. The mutant allele does not
cause disease symptoms when a healthy allele is also
present.
• However, if a parent inherits two mutant alleles, there are
no healthy alleles, so the mutant allele can exert its effect.

19. • In this diagram, the mother of the affected grandson
has inherited a mutated copy from the grandmother,
and the father has inherited a mutated copy from his
family

20. • As shown in the
diagram below, affected
individuals arise when
both of their parents
carry a single mutated
allele and each pass on
that mutated copy to the
child so the child then
has two mutated copies.
A pedigree diagram showing the
inheritance pattern of a
recessive disease

21. • Recessive diseases are more difficult to trace through
family trees because carriers of a mutant allele do not
show symptoms of the disease.
• It therefore appears that the disease has skipped a
generation when it is seen in groups of children
within a family.

22. • The risk of an individual having a recessive disorder
increases when two people who are closely related
have a child together (consanguinity).
• This is because there is a much greater chance that
the same mutant allele will be present in related
parents.

23. X-linked disorders
• X-linked disorders are single gene disorders that
result from the presence of a mutated gene on the X
chromosome.
• Because females (XX) have two copies of the X
chromosome but males (XY) only have one copy, X-
linked disorders are more common in males.
• If a male’s single copy on the X chromosome is
mutated he has no healthy copy to restore healthy
function.

24. • The inheritance patterns of X-linked diseases are
simplified by the fact that males always pass their X
chromosome to their daughters but never to their
sons.
• Like other single gene disorders, X-linked disorders
can be either recessive or dominant.

25. X-linked recessive diseases
• Examples of X-linked recessive disorders include
red-green colour blindness, haemophilia and the
Duchenne and Becker forms of muscular dystrophy.
• X-linked recessive disorders are much more common
in males than females because two copies of the
mutant allele are required for the disorder to occur in
females, while only one copy is enough in males.
The inheritance patterns of X-linked recessive disorders
are as follows:

26. The overall pattern of the disease is characterised by the
transmission of the disease from a carrier mother, who inherited a
copy of the mutant gene from her affected father (this is sometimes
described as a ‘knight’s move’).
A pedigree diagram showing the
inheritance of an X-linked
disorder: 'knight's move'

27. A pedigree diagram
showing the inheritance of an
X-linked mutant gene from
father to daughter
Males always pass their X
chromosome to their
daughters but never their
sons (who receive their Y
chromosome).
These daughters are
described as obligate
carriers.
They generally show no
disease symptoms as they
have one copy of the
mutant gene but also one
copy of the healthy gene.

28. • Female carriers pass
the defective X
chromosome to half
of their daughters
(who are carriers)
and half of their
sons (who will be
affected by the
disease).
• Their other children
will inherit the
healthy copy of the
gene.
A pedigree diagram showing the
inheritance of an X-linked mutant
gene from a carrier mother

29. • Carrier females may show disease symptoms if there
is a chromosome disorder or a problem with X
chromosome inactivation.

30. • X-linked dominant disorders are very uncommon.
• Examples include Rett syndrome (a condition found
almost exclusively in girls that seriously affects brain
development, causing severe disabilities) and some
inherited forms of ricketts (slowed growth and
skeletal development due to vitamin D deficiency).
X-linked dominant disorders

31. • Unlike X-linked recessive disorders, the frequency of
X-linked dominant disorder is similar in males and
females.
• Unlike other dominant diseases, X-linked dominant
disorders cannot be transmitted from father to son
because fathers do not pass their X chromosome to
their sons

32. Terms and Tools to Follow Segregating
Genes
1. A homozygous individual possesses two identical
alleles (i.e. AA or aa). A heterozygous individual
possesses two different alleles (i.e. Aa).
2. Phenotype is the outward expression of a trait (i.e.
tall vs. short; blue eyes vs. brown eyes).
3. Genotype is the actual genetic makeup of the
individual (i.e. AA, Aa, aa).

33. 4. Wild type refers to the most common form. A
mutant is a variant that has under gone a mutation
(change in the DNA).
5. The physical nature of mitosis (chromosome
behaviour) explains the law of segregation. The law
of segregation states that inherited "characters"
(alleles) separate during meiosis, so that each
offspring receives one copy of each allele from each
parent.

34. 6. Punnett squares - convenient method for diagramming
a genetic cross (Law of segregation). Inspection gives
you the genotypic and phenotypic results and ratios.
7. The genotypic ratio for a monohybrid cross is 1:2:1, and
the phenotypic ratio is 3:1.
8. A test cross shows the presence of recessive genes in an
individual with an unknown genotype by crossing them
with an individual homozygous recessive for the genes
in question.

35. Detecting Genetic Disorders
• Cytogeneticists study chromosomes and detect and
analyse hereditary diseases and abnormalities with
the help of pedigrees and karyotypes.
• Molecular tests (genetic tests) can also determine the
presence of alleles linked to diseases and genetic
variations that increase a person's chances of
developing a disease.

36. Pedigrees
• A pedigree is a line of ancestors; descent; lineage;
genealogy; a register or record of a line of ancestors
• Pedigrees can be used to follow a trait through the
generations.
• To study human genetics we will need to examine
patterns of inheritance in an existing population
through pedigree analysis.

37. How Does One Read a Pedigree?
• In cases in which several members of a family have
the same disease,
a pedigree can be used to determine whether the
disease has a genetic component and whether it is
a recessive or dominant phenotype.

38. Pedigree Analysis
• Pedigree charts depict family relationships and
transmission of inherited traits.
• Squares represent males and circles represent
females.
• Horizontal lines indicate parents, vertical lines show
generations, and elevated horizontal lines depict
siblings.

39. • Symbols for heterozygotes are half-shaded, and for
individuals with a particular phenotype, completely
shaded.
• Pedigrees Display Mendel's Laws
• Pedigrees can reveal mode of inheritance, and can
include molecular information, carrier status, and
input from other genes and the environment.

40. • Interpretation of
pedigrees can be
complicated by lack of
information, adoption,
children born out of
wedlock, assisted
reproductive
technologies (i.e.
artificial insemination),
lack of penetrance

41. Karyotypes
• A karyotype is a way to visualize chromosomes. It is
a tool that profiles a person's chromosomes.
• It can detect gross genetic and subtle structural
changes in the chromosomes of a cell population.
• These changes are often associated with specific birth
defects, genetic disorders, and cancers.

42. • A karyogram depicts the karyotype in a snapshot of
the 23 human chromosome pairs; the chromosome
pairs are usually lined up and numbered by size with
the pair of sex chromosomes at the end

43. Matters of Sex
WEEK FOUR

44. Sex-linked traits are a kind of non-Mendelian
inheritance pattern that has traits that are passed on via
the sex chromosomes of an organism.
• Most traits, in humans, are passed down in the somatic
cells of the body via the DNA that is condensed into
chromosomes during mitosis or cell replication.
• However, there are a few traits that are passed down on
the X or Y chromosomes that are known as sex-linked
traits since they are found on the sex chromosomes and
often appear in only one sex as opposed to the other.

45. • Part of the reason that sex-linked traits only show up
in one sex over the other has a lot to do with the
differences between the X and Y chromosome.
• If the male has the recessive trait on the X
chromosome, it will be visible in the phenotype
because there is only one allele that controls that trait.

46. • In humans, most sex-linked traits are found on the X
chromosome but only show up in males due to the
mismatched XY chromosome pair.
• However, there are a few sex-linked traits found on the Y
chromosome only in humans that again, only males show
since females do not have a Y chromosome.
• This does not mean that females cannot show sex-linked
traits.

47. • Sex-linked traits are much more rare in females
because they must have two recessive alleles for that
trait on their X chromosomes.

48. Sex chromosomes and sex-linked
inheritance
• Most animals and many plants show sexual
dimorphism; in other words, an individual can be
either male or female.
• In most of these cases, sex is determined by special
sex chromosomes.
• In these organisms, there are two categories of
chromosomes, sex chromosomes and autosomes (the
chromosomes other than the sex chromosomes).

49. • In females, there is a pair of identical sex
chromosomes called the X chromosomes.
• In males, there is a non-identical pair, consisting of
one X and one Y. The Y chromosome is considerably
shorter than the X.
• At meiosis in females, the two X chromosomes pair
and segregate like autosomes so that each egg
receives one X chromosome.

50. • Hence the female is said to be the homogametic sex.
• At meiosis in males, the X and Y pair over a short
region, which ensures that the X and Y separate so
that half the sperm cells receive X and the other half
receive Y.
• Therefore the male is called the heterogametic sex.

52. • The X and Y chromosomes of some species have
been divided into homologous and non-homologous
regions.
• These differential regions contain genes that have no
counterparts on the other sex chromosome.
• Genes in the differential regions are said to be
hemizygous (“half zygous”) in males.

53. • Genes in the differential region of the X show an
inheritance pattern called X linkage;
• those in the differential region of the Y show Y
linkage.
• Genes in the homologous region show what might be
called X-and-Y linkage.
• In general, genes on sex chromosomes are said to
show sex linkage.

54. • The inheritance patterns of genes on the autosomes
produce male and female progeny in the same
phenotypic proportions, as typified by Mendel’s data
(e.g. both sexes might show a 3:1 ratio).
• However, crosses following the inheritance of genes
on the sex chromosomes often show male and female
progeny with different phenotypic ratios.

55. In fact, for studies of genes of unknown chromosomal location,
this pattern is a diagnostic of location on the sex chromosomes.
• The wild-type eye colour of Drosophila is dull red,
but pure lines with white eyes are available.
• This phenotypic difference is determined by two
alleles of a gene located on the differential region of
the X chromosome.
• When white-eyed males are crossed with red-eyed
females, all the F1 progeny have red eyes, showing
that the allele for white is recessive.

56. • Crossing the red-eyed F1 males and females produces
a 3:1 F2 ratio of red-eyed to white-eyed flies, but all
the white-eyed flies are
• This inheritance pattern is explained by the alleles
being located on the differential region of the X
chromosome; in other words, by X-linkage.
• The reciprocal cross gives a different result.

57. • A reciprocal cross between white-eyed females and
red-eyed males gives an F1 in which all the females
are red eyed, but all the males are white eyed.
• The F2 consists of one-half red-eyed and one-half
white-eyed flies of both sexes.
• Hence in sex linkage, we see examples not only of
different ratios in different sexes, but also of
differences between reciprocal crosses.

58. On the Meaning of Dominance and
Recessiveness
• At the biochemical level, recessive disorders often
result from alleles that cause the loss of function or
production of a normal protein.
• Dominant disorders can result from production of an
abnormal protein that interferes with the function of a
normal protein or result from a gain of function.

59. Genomic Imprinting
• Genomic imprinting is an epigenetic phenomenon
that causes genes to be expressed in a parent-of-
origin-specific manner.
• Forms of genomic imprinting have been
demonstrated in fungi, plants and animals.
• As of 2014, there are about 150 imprinted genes
known in the mouse and about half that in humans.

60. • For most genes, we inherit two working copies - one
from each parent.
• But with imprinted genes, we inherit only one
working copy.
• Depending on the gene, either the copy from mom or
the one from dad is epigenetically silenced.

62. Epigenetics: Definition
• Epigenetics literally means "above" or "on top of"
genetics.
• It refers to external modifications to DNA that turn
genes "on" or "off."
• These modifications do not change the DNA
sequence, but instead, they affect how cells "read"
genes.

63. Examples of epigenetics
• Epigenetic changes alter the physical structure of
DNA.
• One example of an epigenetic change is DNA
methylation — the addition of a methyl group, or a
"chemical cap," to part of the DNA molecule, which
prevents certain genes from being expressed.

64. • Another example is histone modification. Histones
are proteins that DNA wraps around. (Without
histones, DNA would be too long to fit inside cells.)
• If histones squeeze DNA tightly, the DNA cannot be
"read" by the cell.
• Modifications that relax the histones can make the
DNA accessible to proteins that "read" genes.

65. • Epigenetics is the reason why a skin cell looks
different from a brain cell or a muscle cell.
• All three cells contain the same DNA, but their genes
are expressed differently (turned "on" or "off"), which
creates the different cell types.

66. Epigenetic inheritance
• It may be possible to pass down epigenetic changes to
future generations if the changes occur in sperm or
egg cells.
• Most epigenetic changes that occur in sperm and egg
cells get erased when the two combine to form a
fertilized egg, in a process called "reprogramming.“
• This reprogramming allows the cells of the foetus to
"start from scratch" and make their own epigenetic
changes.

67. • However, some of the epigenetic changes in parents'
sperm and egg cells may avoid the reprogramming
process, and make it through to the next generation.
• If this is true, things like the food a person eats before
they conceive could affect their future child.
• However, this has not been proven in people.

68. What is an imprinted gene?
• Imprinted genes are genes whose expression is
determined by the parent that contributed them.
• Imprinted genes violate the usual rule of inheritance
that both alleles in a heterozygote are equally
expressed.

69. Uniparental Disomy
• Uniparental disomy (UPD) occurs when a person
receives two copies of a chromosome, or part of a
chromosome, from one parent and no copies from the
other parent.
• UPD can occur as a random event during the
formation of egg or sperm cells or may happen in
early foetal development.

70. • IN UPD 2 copies of a chromosome come from the
same parent, instead of 1 copy coming from the
mother, and 1 copy coming from the father.
• Angelman syndrome (AS) and Prader-Willi
syndrome (PWS) are examples of disorders that can
be caused by uniparental disomy.

71. How does genomic imprinting occur?
• In genes that undergo genomic imprinting, the parent
of origin is often marked, or “stamped,” on the gene
during the formation of egg and sperm cells.
• This stamping process, called methylation, is a
chemical reaction that attaches small molecules called
methyl groups to certain segments of DNA.

72. What causes genomic imprinting?
• Both of these conditions are caused by deletions or
other mutations in the same region of chromosome
15.
• However, part of this region is imprinted (or
inactivated) on the maternally inherited chromosome
(the PWS region), and part is imprinted on the
paternal chromosome (the AS gene, which is called
UBE3A).

73. How is genomic imprinting
maintained?
• Parental imprints are established during
gametogenesis as homologous DNA passes uniquely
through sperm or egg; subsequently during
embryogenesis and into adulthood, alleles of
imprinted genes are maintained in two
"conformational"/epigenetic states: paternal or
maternal.

74. • Silencing usually happens through the addition of
methyl groups during egg or sperm formation.
• The epigenetic tags on imprinted genes usually stay
put for the life of the organism. But they are reset
during egg and sperm formation.
• Regardless of whether they came from the male or
female, certain genes are always silenced in the egg,
and others are always silenced in the sperm.

75. Imprinted Genes Bypass Epigenetic
Reprogramming
• Soon after egg and sperm meet, most of the
epigenetic tags that activate and silence genes are
stripped from the DNA.
• However, in mammals, imprinted genes keep their
epigenetic tags.
• Imprinted genes begin the process of development
with epigenetic tags in place.

76. • Imprinting is unique to
mammals and flowering
plants.
• In mammals, about 1%
of genes are imprinted.

77. Imprinting is required for normal
development
• An individual normally has one active copy of an
imprinted gene.
• Improper imprinting can result in an individual
having two active copies or two inactive copies.
• This can lead to severe developmental abnormalities,
cancer, and other problems.

78. Why Imprint? The Genetic Conflict
Hypothesis
• There a number of hypotheses to explain why
imprinting happens in mammals.
• One of these, the Genetic Conflict hypothesis,
supposes that imprinting grew out of a competition
between males for maternal resources.
• In some species, more than one male can father
offspring from the same litter.

79. for example
• A house cat can mate more than once during a heat
and have a litter of kittens with two or more fathers.
• If one father's kittens grow larger than the rest, his
offspring will more likely survive to adulthood and
pass along their genes. So it's better for the father's
genes to produce larger offspring.
• The larger kittens will be able to compete for
maternal resources at the expense of the other father's
kittens.

80. • On the other hand, a better outcome for the mother's
genes would be for all of her kittens to survive to
adulthood and reproduce.
• The mother alone will provide nutrients and
protection for her kittens throughout pregnancy and
after birth.
• She needs to be able to divide her resources among
several kittens, without compromising her own needs.

81. • It turns out that many imprinted genes are involved in
growth and metabolism.
• Paternal imprinting favours the production of larger
offspring, and maternal imprinting favours smaller
offspring.
• Often maternally and paternally imprinted genes work in
the very same growth pathways. This conflict of interest
sets up an epigenetic battle between the parents -- a sort
of parental tug-of-war.

82. Genetic Polymorphism
WEEK SEVEN

84. Population Genetics
WEEK EIGHT

85. • Population genetics describes the behaviour of alleles
in populations by focusing on the forces that can
cause allele frequencies to change over time.
• “Allele frequency change over time” is simply a
definition of “evolution”.

86. • Thus, population genetics is that branch of genetics
concerned with the evolutionary processes of natural
selection, genetic drift, mutation, migration, and non-
random mating.
• Population genetic approaches can be used to
understand the consequences of these processes
individually or in combination.

88. • Consider an analysis of a local population with
respect to a phenotype determined by two alleles at a
single locus.
• The human MN blood group is an extremely simple
system.
• It is characterized by a single locus with only two
alleles, M and N.
• The alleles are codominant (both alleles are
detectable in heterozygotes).

89. ALLELE & GENOTYPE FREQUENCIES IN SURVEY OF BRITISH POPULATION:
Phenotype Genotype #M alleles #N alleles
298 M
489 MN
213 N
TOTAL
1000
298 MM
489 MN
213 NN
1000
596
489
0
1085
0
489
426
915

90. Genotype frequency is relative proportion of genotype:
Proportion of MM genotype = 298/1000 = 0.298
Proportion of MN genotype = 489/1000 = 0.489
Proportion of NN genotype = 213/1000 = 0.213
Total = 1.000
The allele frequency of the M allele is the relative proportion of the allele:
Proportion of M allele =1085/2000=0.5425
Proportion of N allele = 915/2000 =0.4575
Total=1.000
• If we let p = the allele frequency of M and q= the allele frequency of N,
then q = 1-p.

91. THE HARDY-WEINBERG PRINCIPLE
• We can use knowledge of allele frequencies to make
inferences about patterns of mating, selection on
certain alleles, migration between populations, etc.
• Allele frequencies are more useful than genotype
frequency because alleles rarely undergo mutation in
a single generation, so are stable in their transmission
from one generation to the next.
• In contrast, genotypes are not permanent.

92. • They are broken up by the processes of segregation and
recombination that take place during meiosis.
• Furthermore, we can deduce the expected genotype
frequencies in the next generation from knowledge of
only the allele frequencies in the previous generation.
• First, consider that for diploid organism with two
different alleles at a locus, a gamete has an equal chance
of containing either of the two alleles (equal segregation--
Mendel's first law)

93. Individual Gamete types Gamete contribution Gamete frequency
0.298 MM All M
0.489 MN 1/2 M
1/2 N
0.213 NN

94. Multifactorial Traits
WEEK NINE