Lecture #4

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What we already should know:
 Structure and function of DNA
 Structure and composite regions of HG
 DNA replication
 DNA recombination
 DNA damage and mutations
 DNA repair mechanisms
 Major 3 groups of Human Diseases based on etiological share of
inherited and environmental factors

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Genes, Environment & Inheritance
Terminology to know:
 Alleles - different forms of a gene at a locus, e.g. SNPs, gene CNVs, etc;
 Haplotype - a set of closely linked DNA markers at one locus which are
inherited as a unit e.g. haplotype of SNPs , haplotype of gene combinations;

Dominant model Recessive model

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Odds ratio

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2
1
1 0.5
0.25
0.5
0.125
0.25 0.0625
C-T A-T C-A A-A C-T A-T C-A А-А

rs6815306 – rs17008675 haplotype

 Genotype –
 at global level, the genetic (DNA) make-up (ID) of an organism, or
 at gene level, the genetic composite of alleles at a specific locus; 3
Genes, Environment & Inheritance

Terminology to know:
 Homozygousity - both alleles at a locus are identical ;

 Heterozygousity – alleles at a locus are different;

 Hemizygousity – there is one chromosome (Chr.) of a Chr. pair (e.g. X-linked

genes in males) or chromosomal segment (e.g. an absence of a gene on one of
Chr.-s due to CNV or DNA recombination, such as seen in cancer cells).

 Autosomal inheritance involves traits that are encoded by the 22 pairs of

human autosomal chromosomes;

 X-linked inheritance refers to genes located on the X chromosome;

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Genes, Environment & Inheritance
Terminology to know:
 Phenotype – recognizable characteristics determined by the genotype (e.g. eye
color) and /or by the genotype - environment interaction, e.g. normal traits
such as height, intelligence …or diseases.

Many Genes

Environmental
Life Style
Factor(s)

Single Gene Phenotype Epigenetic

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Genes, Environment & Inheritance
Genetic diseases can be classified:
 by inheritance mode –
 autosomal dominant,
 autosomal recessive,
 X-linked or Y-linked (mutation in one of 104 genes),
 mtDNA-linked (mutation in one of 37 genes) ;
 by a molecular mechanism –
 mutations in single genes,
 complex genetic abnormalities,
 gene-gene (G x G) interactions,
 gene-environment (G x E) interactions,
 epigenetic changes,
 non-heritable DNA mutations in somatic cells.
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Genes, Environment & Inheritance

What is a differenence in genetic and inherited

diseases?

Both Inherited and sporadic diseases can be genetic diseases,

with a difference is in heritability :
 Inherited diseases involve genetic aberrations in germ
cells.
 Sporadic diseases involve genetic aberrations in
somatic but not germ cells. Thus, they are lacking of
heritability (i.e. some types of cancers).
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Genes, Environment & Inheritance

Since 1966 - Mendelian Inheritance in Man(MIM)

Since 1987 - OMIM – www.omim.org
 20699 entries on:
 ~94% - autosomal disorders;
 ~6% - X-linked;
 0.3% - Y-linked disorders;
 0.3% - mitochondrial DNA related disorders
 and entries on genes.
 Some journals up until now require to have MIM# of entry in the
manuscript, when information on a disease or gene is presented.
 The majority of entries involve single genes.
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Genes, Environment & Inheritance

The majority of MIM entries involve single genes!?

The core information comes from MZ and/or DZ twin studies

based on classical genetics of diseases;
 the environment shared by DZ and MZ twins is similar, but
 Shared genetic identity is different
 DZ twins ~50% like the other siblings
 MZ twins </= 100%
Therefore, twins are a popular model for assessing the relative
contributions of genes and environment in a disease.

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Autosomal Dominant Disorders, ASDD

1. The characteristic feature in a pedigree of autosomal dominant

inheritance is a vertical mode of transmission.
2. Disorder can appear in every generation of the pedigree.
3. Both males and females are affected and offspring are at 50%
risk.

Is Dr. R. Trent
right? 50% risk ?

In monogene disorder:
A/A vs. A/a + a/a

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ASDD

Some features of ASDD

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 ASDD - Examples:
The Fragile X syndrome (CGG) repeat is in the 5’ flanking region of the
gene (normally 10–50 repeats). Expansion beyond 200 repeats is
associated with methylation (silencing) of the FMR1 gene on X-chr. Interspersed triplet repeats
Xq27.3, i.e. a loss of function. The absence of protein causes
abnormal neurodevelopment and, subsequently, mental retardation.

For Huntington disease, the (CAG)n triplet repeat (normally 6–26) is

located within the HTT gene’s first exon (Chr. 4p16.3). The repeat is
a CAG, which codes for glutamine. Therefore, adding more
polyglutamines to this protein (called huntingtin) will interfere
with its structure or function. Studies in humans and mouse models
suggest that huntingtin has its deleterious effect through a gain of
function.

For Myotonic dystrophy, the (CAG) repeat is located in the 3’ flanking

region (normally 5–34 repeats). Mildly affected patients have 50–80
repeats, while severely affected individuals - =/> 2 000. How the
expansion at the 3’ non-coding region affects function of the
myotonic dystrophy gene (DMPK; Chr. 19q13.32).
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ASDD - Examples: Huntington disease

Interpretation of (CAG)n repeat numbers

in Huntington disease
Number (n) Interpretation of phenotype
<27 Normal
27-35 Normal but there is risk that offspring will develop Huntington
disease
36-39 This is associated with the Huntington disease phenotype but
there is the potential for reduced severity. Some with these repeat
numbers might not develop Huntington disease. There is the
chance that offspring will develop Huntington disease.
>40 Huntington disease
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ASDD – Peculiarities :

There are a number of disorders in which triplet Anticipation of the disease

repeat expansion is the basis for increasing severity
in subsequent generations.

The observation related to instability in the repeat

numbers uncovered the possibility that repeats
could expand or contract slightly when
transmitted through sperm or ovum, respectively:
Spermatogenesis or Oogenesis. These observations
explain for example,
• Why is the female parent who presents
this risk in Myotonic dystrophy;
• Why cases of juvenile Huntington disease
invariably inherited the mutant HTT from
their fathers.
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Autosomal Recessive Disorders, ASRD

1. The appearance of an autosomal recessive disorder in a pedigree

gives rise to a horizontal rather than a vertical pattern. This occurs
because affected individuals tend to be limited to a single sibship.
2. Disorder can not appear in every generation of the pedigree.
3. Both males and females are affected
4. Two heterozygous individuals , who are clinically normal, can leads to
an 25% ASRD risk for an offspring
Is Dr. R. Trent
right? 25% risk ?

In monogene disorder:
A/A + A/a vs. a/a

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ASRD – Example : Hereditary hemochromatosis

 Hereditary hemochromatosis is an ASRD of iron

metabolism.
 Frequency 1 to 8, with the highest incidences found in
populations of Celtic origin.
 Symptomes –
 non - specific lethargy or arthralgia , and less common,
diabetes mellitus, liver disease, and generalized
pigmentation;
 specific complications cardiomyopathy and
hepatocellular carcinoma
 Threatment – early diagnosis followed by a periodic
venepuncture
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ASRD – Example

Hereditary hemochromatosis
is mostly caused by
mutation in HFE gene (type
1), resulting in AA change:
1. Cys 282 Tyr;
2. His 63 Asp;
3. Ser 65 Cys.
First mutation alters ability of
HFE protein to bind mβ2,
and subsequently , to
transferrin receptor I
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ASRD – Example : Hereditary hemochromatosis
Gene-Envireonment (GxE) interaction in
Hereditary hemochromatosis
 An individual with hereditary hemochromatosis has the genetic
predisposition, but there are environmental factors, and perhaps other
genetic contributors, that will determine if there will be progression to
clinical hemochromatosis.
 An important environmental factor is sex – the male to female ratio for
hemochromatosis is as high as 3:1 even though it is an autosomal. An
explanation for this is that menstruation is protective for women.
 The distinction between hereditary hemochromatosis and clinical
hemochromatosis is important, e.g Cys 282 Tyr mutation in HFE:
 28% of males & 1.2 % of females.
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X-Linked Disorders , X-LD

 X-linked disorders result from mutations in genes on the X chromosome.

 Disorder can fully appear in males of the pedigree, as they are hemizygous
(only have one) for X chromosome.
 Females, who have two X chromosomes, will be carriers of the defect in the
majority of cases, and so they are usually asymptomatic.
 Some females of offspring
may be symptomatic due to
Lyonization of normal X Chr.
 For each son 50% risk
Inheritance via maternal linage

In monogene disorder:
X/x + X/Y vs. x/Y

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X-Linked Disorders – Example: Hemophilia

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X-Linked Disorders – Example: Hemophilia
Coagulation cascade

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X-Linked Disorders , X-LD

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X-Linked Disorders – Example: Hemophilia

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 Human Monogenic Diseases, Modes of Inheritance, and Associated Genes
Disease Inheritance Gene Responsible

Phenylketonuria (PKU) AR Phenylalanine hydroxylase (PAH)

Cystic fibrosis AR Cystic fibrosis conductance transmembrane regulator (CFTR)
Sickle-cell anemia AR Beta hemoglobin (HBB)
Albinism, oculocutaneous, type II AR Oculocutaneous albinism II (OCA2)
Huntington's disease AD Huntingtin (HTT)
Myotonic dystrophy type 1 AD Dystrophia myotonica-protein kinase (DMPK)
Hypercholesterolemia, type B AD Low-density lipoprotein receptor (LDLR); apolipoprotein B (APOB)
Neurofibromatosis, type 1 AD Neurofibromin 1 (NF1)
Polycystic kidney disease 1 and 2 AD Polycystic kidney disease 1 (PKD1) and polycystic kidney disease 2 (PKD2), respectively
Hemophilia A X-linked rec. Coagulation factor VIII (F8)
Muscular dystrophy, Duchenne type X-linked rec. Dystrophin (DMD)
Hypophosphatemic rickets, X-linked
X-linked dom. Phosphate-regulating endopeptidase homologue, X-linked (PHEX)
dominant
Rett's syndrome X-linked dom. Methyl-CpG-binding protein 2 (MECP2)
Spermatogenic failure,
Y-linked Ubiquitin-specific peptidase 9Y, Y-linked (USP9Y)
nonobstructive, Y-linked
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mtDNA linked inheritance

mtDNA is cyclic dsDNA of 16.6Kb with 37 protein

encoding genes.
 Mitochondria are essential for eukaryotic cells:
 production of energetic butteries of during oxidative
phosphorylation and storage , i.e. ATP;
 involvement of a number of cellular and metabolic
processes:
1. Apoptosis;
2. Production of reactive oxygen species; and
3. Cellular oxidation and reduction.
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mtDNA linked inheritance

Features which suggest a mtDNA disease are:

(1) Maternal inheritance, i.e. both males
and females can be affected but the disorder
is only transmitted by females (Figure 2.10);
Pedigree depicting mtDNA
(2) Energy production is preferentially inheritance
impaired so likely diseases are
encephalopathies, myopathies and
cardiomyopathies;

(3) Variable expression in affected

individuals.

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mtDNA-linked
diseases

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Genes, Environment & Inheritance
Phenotype – recognizable characteristics determined by the genotype and /or
by the genotype -environment interaction, e.g. eye color, height, intelligence;

Many Genes

Environmental
Life Style
Factor(s)

Single Gene Phenotype Epigenetic

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Genes, Environment & Inheritance

 Other forms of Genetic Inheritance:

 Gene-gene Interaction, e.g. thalassemia;
 Mitochondrial Inheritance;
 Uniparental Disomy ;
 Mosaicism & Chimerism;
 Chromosomal Disorders.

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 Home work
Watch the following youtube videos and prepare short talk s with slide-show:
 Myotonic dystrophy https://youtu.be/zMxaeVbqyMM
 Duchenne & Becker muscular dystrophy https://youtu.be/DGOmN6rnsNk

Go to “GENE” database of the NCBI https://www.ncbi.nlm.nih.gov/gene

and find gene cards of the following genes and become acquainted with:
 Phenylalanine hydroxylase (PAH)
 Cystic fibrosis conductance transmembrane regulator (CFTR)
 Beta hemoglobin (HBB)
 Dystrophia myotonica-protein kinase (DMPK)
 Dystrophin (DMD)
 Ubiquitin-specific peptidase 9Y, Y-linked (USP9Y)
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