OPT102

Genetics: Sex, Inheritance & Human Disease

Dr Annwyne Houldsworth

Route map

• Mitosis, meiosis• Genotype vs phenotype• Haploid, diploid• Chromosomes• DNA structure• DNA code, translation, transcription• Mutation• Autosomal dominant/recessive• X linked mutations• Population genetics• Gene therapy

Two organisms with identical genotypes normally differ in their phenotypes. The same genotype, since their genomes are identicalNever have the same phenotype (phenotypes may be very similar) Identical twins can be distinguished by their fingerprints, which are never completely identical.

Monozygous (identical twins)

Heterozygotic twins

• Fraternal twins• Fertilization of two

eggs• Dizygotic • Biovular

Meiosis

• Meiosis is a different kind of cell division to mitosis. • Used to produce male and female gametes.• Human body cell contains 46 chromosomes arranged in

23 pairs. • The gametes are sperm or eggs, and only contain half as

many chromosomes, haploid (23). • This is why meiosis is sometimes called reduction

division.

Meiosis

Fertilization

• At fertilization, the nuclei of the sperm and an egg join to form the zygote.

• The zygote contains 23 pairs of chromosomes - 23 single chromosomes from the sperm

• 23 single chromosomes from the egg • Creating the correct number of 46 chromosomes for all

body cells, diploid. • Also means the zygote contains a complete set of

chromosomes from each parent.

Conception

Overview of terms

• Gamete – cell with half the normal number of chromosomes, and only used for sexual reproduction

• Zygote – cell formed when two gametes combine• Fertilization – term to describe the joining of two

gametes• Haploid – having half the normal number of

chromosomes• Diploid – having the normal number of chromosome

Mitosis cell division

• Asexual reproduction• Growth and repair• Cells identical to parent

cell• 46 chromosomes each

There are always genetic and environmental factors that govern health and illness

Your genes

You

The influences over your genes

Genotype• An organism’s full hereditary information• You are what you are as a result of your genes and the influences over

your genes

Phenotype• An organism's actual observed properties, such as

morphology, development, or behavior. • Observable expression of genes

Genotype phenotype relationships

Chromosome

Homologous chromosomes• The length of chromosomal arms equal• The placement of the centromere• Same number of each homologous chromosome • Humans are diploid

Chromosomes

• Chromosomes are linear arrangements of condensed deoxyribonucleic acid (DNA) and histone proteins

• Form a complex called chromatin.• Homologous chromosomes are made up of chromosome pairs

-same length, -centromere position,

• -staining pattern, for genes with the same corresponding genes.

• One homologous chromosome is inherited from the organism's mother

• The other is inherited from the organism's father.

Chromosomes• Karyogram• Karyotype• Number of chromosomes• Type of chromosomes

Progression to condensed chromatin

DNA

https://g10biodna-a.wikispaces.com/(b)+DNA+Structure

How DNA fits together

DNA blue print for life

Banister rail of the staircase• Backbone of DNA is a repeated pattern of sugar and

phosphate groups deoxyribose Nucleotides as stair rungs • Thymine: binds to adenine via 2 hydrogen bonds• Adenine: binds to thymine via 2 hydrogen bonds• Cytosine: a pyrimidine derivative and forms 3 hydrogen

bonds• Guanine: Derivative of purine and is paired with cytosine

Nucleotides

Notes on DNA nucleotidesA DNA molecule is made up of four different chemical compounds called nucleotide or organic bases, and they are as follows:• (A) or Adenine is a nucleobase with a variety of roles in

biochemistry including cellular respiration, in a form of ATP and NAD and FAD and protein synthesis.

• (G) or Guanine is paired with cytosine. Guanine is a derivative of purine, consisting of a fused pyrimidine - imidazole ring system

• (T) or Thymine is a pyrimidine base that is a component of a DNA• (C) or Cytosine is a white pyrimidine occuring in nucleic acids and

forms a pair with Guanine

In all organisms, Adenine and Thymine always pair up, and Guanine and Cytosine always match up.

Codon

Uracil

Codons table

Codons and amino acids

Transcription, Translation of DNA

Alleles

• DNA made up of two strands• Each strand of a gene called an allele

homozygote/heterozygote

• We have 2 alleles to each gene

• Our parents pass on two sets of genes.

• Each with 2 alleles

• These alleles, for each gene, may be identical or they may

be different.

• Having two possible forms of a gene contributes to natural

human variation.

• Identical alleles-homozygous

• Different alleles-heterozygous

Segregation of Alleles

• During division of sex cells, the chromosome pairs are split in two.

• This will segregate the different alleles.• For a heterozygous genotype AaBb, the new sex cell or

gamete will possess an AB, aB, Ab, or ab genotype.• This segregation can be predicted by drawing a punnet

square.

Eggs or Sperm(gametes)Cells of

Ovary or Testis

A

a

A a

AA Aa

aA aa

Parent 1Pa

rent

2

Segregation of Alleles: The Punnet Square

gametes

• During division of sex cells, the chromosome pairs are split in two.

• This will segregate the different alleles.• For a heterozygous genotype AaBb, the new

sex cell or gamete will possess an AB, aB, Ab, or ab genotype.

• This segregation can be predicted by drawing a punnet square.

Polymorphism (SNP)

Spontaneous Mutations

• Tautomerism- A base changed by repositioning H atom

• Depurination- Loss of purine base (A or G)

• Deamination- normal base to atypical base (C-U)

• Transition- Purine A-G or pyrimidine C-T

• Transversion- Purine becomes pyrimidine or vice versa

• Induced mutations

Genetic mutation

• Errors in copying genetic information

• Changes is base pair sequence

• Germline or somatic mutations

• Many mutations are deleterious

• Many eliminated by natural selection

• Survival of species enhanced by genetic

change

• Survival of individual demands genetic stability

123rf.com

Types of Genetic Mutation

• Point mutation

• Inversion

• Deletion

• Translocation

Chromosomal Structure

• Amplifications (or gene duplications)

• Deletions of large chromosomal regions

• Chromosomal translocations

• Interstitial deletions- intra-chromosomal deletion

• Chromosomal inversions, reversing the orientation

• Loss of heterozygosity- loss of an allele

mthfr.net

Mendelian inheritance.

• 19th Century monk called Gregor Mendel, noticed that recessive characteristics can be expressed that are not visible in the parent.

• These general principles of inheritance are termed Mendelian Inheritance Patterns.

• Based on sexual reproduction.• Three main processes:

• Segregation of alleles at cell division.• Independent assortment of chromosomes at cell division.• Crossovers (gene recombination) at cell division.

Molecular Genetics

• Autosomal recessive- (25%) homozygous

• Autosomal dominant- (50%) heterozygous

• X-linked recessive- (all heterozygous males affected)

• X-linked recessive- (>50% normal expression normal phenotype)

• X-linked dominant- male foetuses do not develop

• X-linked dominant- females are severely affected

leavingbio.net

Consequences of Mutation

• Lethal mutation (phenotype incapable of reproduction)

• Morphological mutation (outward appearance)

• Conditional mutation (certain environmental conditions)

• Amorphic, loss of function, null mutation (often recessive)

• Neomorphic, gain of function mutation (dominant)

• Antimorphic mutation, dominant negative (altered function)

• Suppressor

Chromosomal Fragmentation• During division chromosomes may break.• This may be repaired or pieces may ‘cross over’

or ‘translocate’.• Effect proportional to amount of genetic material

involved and its importance.• Example is Fragile X - a common cause of

congenital mental retardation.

Genetic Disorders

• Genetic disorders can arise in a number of ways:• Mutation during foetal development.• Inheritance of a mutant allele from an ancestor.• Damage to a chromosome.• A change in the number of chromosomes.• Mutation by environmental factors.

• Inheritance of a faulty, mutated allele is dependent on:• Whether the allele is dominant or recessive.• Whether the mutation is on the 22 pairs of autosomes or on

the pair of sex chromosomes.

Cystic Fibrosis

• Affects 1 in 2500 new-borns, heterozygote carrier rate estimated at 1 in 25 individuals.

• Abnormality in membrane transport mechanisms leading to lack of water in body secretions - sticky mucus in lungs, sticky pancreatic secretions, concentrated sweat.

• Mutation to CFTR gene on Chromosome 7.• Large gene 250000bp - mRNA= 6129bp

CFTR

• Acts as a chloride channel.• CF mutation is a deletion of CTT at codon 508 and at

600 other sites on the gene.

Normal GAA AAT ATC ATC TTT GGT GTT TCCProtein Glu Asn Ile Ile Phe Gly Val SerPosition 504 505 506 507 508 509 510 511

CF GAA AAT ATC AT - - -T GGT GTT TCCProtein Glu Asn Ile Ile Gly Val Ser

Huntington’s Chorea Disease• Autosomal dominant mutation

mHTT• Either copy of the gene HTT • Trinucleotide repeat• Codes for protein Huntingtin, Htt• Htt interacts with over 100 other

proteins• Neurodegenerative disease• Chorea, jerky, writhing, body

movements• Expansion of a CAG triplet repeat

Down Syndrome (trisomy)

• One of most common serious chromosomal disorders = Trisomy 21.

• 95% of affected individuals = Trisomy 21 secondary to non disjunction during meiosis.

• Maternal chromosomes implicated in 95% of these, and 80% from meiosis I.

• Approx 4% of Down Syndrome babies result from unbalanced translocation (most = fusion of long arm 14 to long arm 21.)

• Other unbalanced translocations = 21 to 21 (22 to 21).• Less than 3% of Downs = mosaicism (47 +21 cells as

well as normal euploid line)

Trisomy 21

Turner Syndrome (45X)• Absence or partial copy of X chromosome• X usually inherited from mother• Abnormal X usually from father• Can have mosaic characteristics• Diagnosed by amniocentesis or chorionic Villus

sampling • Monosomy

Kleinfelter (47XXY)

• Most common chromosomal disorder• 1:500-1:1000 live male births• Less muscle strength• Less testosterone• Gynecomastia

X-linked Inheritance

• Females (XX), males (XY)

• Males hemizygous for mutation affected (1/100)

• Females homozygous for gene mutation affected (1/10,000)

• Carrier females have one copy of mutation

• Carriers do not usually express phenotype

• Lyonisation leads to varying degrees of clinical expression in

carriers

• Haemophilia FVIII, Duchene muscular disease, red/green

colour blindness

X

X

Normal (X) Haemophiliac (X)

FemaleXX

MaleXY

X-linked inheritance

Normal (Y)

Carrier Normal

Haemophiliamale

Haemophilia carrier female

How do genes affect eye colour?

Allele combinations

Eye colour determined by• Melanin found in your iris with white collagen fibres• Different shades of grey, green and hazel• Light travels through a relatively melanin-free iris• Collagen fibres within the iris scatter the short blue

light to the surface • Creating the blue appearance of the iris• Melanin contribute brown colour

Examples of inherited eye conditions

• strabismus (cross-eyes) • amblyopia (lazy eye) refraction errors such as • myopia (nearsightedness)• hyperopia (farsightedness) • astigmatism.

Familial Hypercholesterolaemia.

• Autosomal dominant disorder affecting 1 in 500 individuals and 5% of heart attack patients younger than 60.

• Fault in cholesterol metabolism = lack of functional LDL receptors inside cells.

Familial Hypercholesterolaemia.

Failure to metabolise LDLs leads to increased levels in blood

• Autosomal dominant disorder affecting 1 in 500 individuals and 5% of heart attack patients younger than 60.

• Fault in cholesterol metabolism = lack of functional LDL receptors inside cells.

LDL receptor gene mutations

Population genetics.

• The processes of mutation and Mendelian inheritance lead to variance in every persons genotype.

• This variation has implications not only for a persons external features but for metabolic function and for health status.

• This variation occurs in multiple genes and multiple genes contribute to the majority of life processes.

• So population genetics and multifactorial inheritance are important in our understanding of the biological variation found in patients/clients.

• Population genetic data can be used to assign “risk” and to design genetic screening programme.

Ethnicity and genotype

Hardy – Weinberg equilibrium

• A key concept in population genetics – used in clinical genetics to explain why in a large population with random mating, allele frequencies do not change from generation to generation.

• Also explains how for any genetic locus, the genotype frequencies are determined by the relative frequencies of the alleles at that locus.

• Consider a single gene locus with two alleles A and a.• Frequency of allele A in gametes(egg, sperm) = p.• Frequency of allele a in gametes = q

Hardy – Weinberg equilibrium• A key concept in population genetics – used in clinical genetics to

explain why in a large population with random mating, allele frequencies do not change from generation to generation.

• Also explains how for any genetic locus, the genotype frequencies are determined by the relative frequencies of the alleles at that locus.

• Consider a single gene locus with two alleles A and a.• Frequency of allele A in gametes(egg,sperm) = p.• Frequency of allele a in gametes = q

Genotype Frequencies in Children.

Paternal gametesA (p) a (q)

A (p) AA (p2) Aa (pq)

Maternal gametes

a (q) Aa (pq) aa (q2)

Genotype: AA Aa aa

Frequency: p2 2pq q2

stable over the generations

Hardy Weinberg In Action

• Useful in assessing risk for genetic counselling.• Cystic fibrosis occurs in 1 in 2000 – thus homozygous recessive (q2) =

1/2000.• Frequency of mutant allele (q) is the square root of 2000 = 1/45 or

0.022.• Frequency of normal allele is p=44/45 or 0.978.• Heterozygote carrier rate is 2pq = 2 x44/45 x 1/45 = 1/23 or 0.043.• So approx 4% of population are heterozygote carriers.

biological processor disease

map

clone gene

diagnostics

preventative medicine

understand biologicaleffect

genetherapy

drug therapy

Molecular genetics : Research & Applications

Gene therapy

Symbols for Pedigree Analysis