GENETICS

Definitions

• Penetrance - The probability that an individual who is ‘at-risk’ for the disorder (ie- carries the gene) develops (expresses) the condition. May be age dependent.

• Expression - The characteristics of a trait or disease that are outwardly expressed. Eg-myotonic dystrophy: myotonia, cataracts, narcolepsy, frontal balding, infertility.

Penetrance and Expressivity

• Penetrance: Proportion that expresses a trait– Complete: P=1.0 or 100%

– Incomplete (“reduced”): P<1.0 or < 100%

• Expressivity: Severity of the phenotype– Expressivity may vary

• Between families (interfamilial) or

• Within families (intrafamilial)

• TRY NOT TO CONFUSE “VARIABLE EXPRESSIVITY” WITH “INCOMPLETE PENETRANCE”

Chromosomes, Genes and Proteins

Genes are on Chromosomes

Genes may encode proteins or RNA

Chromosome Facts

• Chromosomes replicate during S phase• Chromosomes recombine during Pachytene• Recombination is an obligate activity• Sex chromosomes recombine with each other

Cell Division: Meiosis

• Occurs in germ cells– Oogenesis– Spermatogenesis

• Preserves the diploid chromosome number in human cells

• Genetic diversity– Paternal and maternal chromosome combination at

fertilization– Crossing over

Meiosis Creates Gametes

And provides a basis for genetic recombination!

Genetic Recombination

• Crossing Over• Resolution• Recombinant Chromosomes

– OBLIGATE ACTIVITY– FEMALE RECOMB. RATES HIGHER THAN MALE– INCREASED RATES AT TELOMERES– PARADOX: SHORT ARMS SHOW MORE THAN LONG ARMS– 1cM is 1 Mb on long arms, but short arms are 2 cM per Mb and

the Yp-Xp pseudoautosomal region is 20 cM per Mb.

Genes

• Units of heredity• Encode proteins (and some RNAs)• Human genetics is the study of gene variation in

humans• ‘Gene’ as a term is used ambiguously to refer

both to the ‘locus’ and the ‘allele’ ie- There is only one locus but two alleles in a given individual.

• Sequencing in both genome projects took place upon multiple alleles; this has led to some assembly confusions.

• Ultimately want a haploid genome map.

What is genetics?

Genetics – study of single or a few gene and their phenotypic effectGenomics – a study of all the genes in the genome and their interaction

DNA microarray analysis of tumor

“Genetics is the study of genes”-- Griffiths et al, Introduction to Genetic Analysis

What is a gene?

Genes are DNA segments that have a functional role in the cell and are responsible for inheritance of traits

Genes comprise only about 2 % of the human genome; the rest consists of non-coding regions

“A gene is a section of a threadlike double helical molecule called DNA”-- Griffiths et al, Introduction to Genetic Analysis

Inheritance

Gregor Mendel(1860s)

Inheritance occurs in a discrete manner

Cross offspring - get ¾ purple

Cross purple and white - get all purple

Pea flowers can be purple or white

Mendelian inheritance

Polydactyly is a dominant trait

A A a a

• There are 2 copies of each gene in each cell, and a single gene determines a single trait

phenotype

genotype

• Genes have alleles that are dominant or recessive

A adominant allele recessive allele

A A A a A a a a

Alleles reassort randomly in offspring

Non-Mendelian inheritance

Some traits are determined by 2 or more genes, each with multiple alleles

3 different genes determine color and pattern in the foxglove

flower

Continuous traits are determined by large numbers

of genes

Human height is a continuous trait

Genetics and environment

Phenotype is determined by BOTH genotype AND environment

Example: Adult onset diabetes

• Susceptibility genes are inherited

• Environmental factors influence disease onset (eg. obesity)

Genetic structures

Cells

Chromosomes

Genes

DNA

Human chromosomes

22 pairs of autosomes + 2 sex chromosomes (XX or XY)

Sex chromosomes and inheritance

• Many genes are carried on the X and not the Y chromosome

Example: red-green color blindness is X-linked

• Recessive alleles on the X will appear dominant in males (no other allele present to mask the recessive phenotype)

X chromosome inactivation

Inactivation is random during development

Color pattern seen in female calico cats due to random X

chromosome inactivation

• X chromosome has many more genes than the Y chromosome

• Females have 2 Xs

One X must be inactivated to preserve gene dosage

Barr bodies in female cells

Inactive Xs condense to form Barr bodies during development

DNA structure

• Only 4 nucleotides (bases) make up all DNA:

A (adenine)

C (cytosine)

T (thymine)

G (guanine)

- T

- G

- A

- C

• DNA strands are antiparallel

• The two ends (5 prime and 3 prime) are not equivalent

Autosomal Dominant Disorders

• Manifested in heterozygous state• At least one parent is usually affected• Both males and females are affected and both can

transmit the condition• If unaffected marries an unaffected – child has one

chance in two of having the disease• Many new mutation seem to occur in germ cells of

relatively older father• Clinical feature can be modified by reduced

penetrance and variable expressivity• In many condition, the age at onset is delayed.

(Huntington disease)

Autosomal Recessive Disorders

• Single largest category of mendelian disorders.• Results only when both alleles at a given gene locus

are mutant.• Traits does not usually affect the parents but siblings

may show the disease• Siblings have one chance in four of being affected• Equal numbers of affected males and females• Affected persons who marry normals have only

normal offspring

Autosomal Recessive Disorders

• The expression of the defect tends to be more uniform than in autosomal dominant disorders

• Complete penetrance is common

• Onset is frequently early in life

• Eg

– Phenylketonuria

– cystic fibrosis

X-linked Dominant Inheritance

• Each generation usually has an affected individuals• Affected males with normal mates have no affected

sons and no normal daughters• Both sons and daughters of an affected

heterozygous female may be affected

X-linked Recessive Inheritance

• Affected fathers never transmit the trait to their sons

• Unaffected parents may have affected offspring

• Generally there are more affected males than females

The Central Dogma

DNA replication

• Replication is semiconservative

• Each child strand has one of the parent strands

• Replication only occurs in the 5’ to 3’ direction

Replication fork

Transcription

DNA encoding gene messenger RNA

Translation

messenger RNA protein

Amino acids

tRNA

mRNA ribosome

Protein function

• Proteins are the primary molecules responsible for cellular function

• They have complex structure and some can perform chemical reactions (enzymes):

DNA structure

Protein structure (hemoglobin)

RNA function

• Some specialized RNA molecules have function:

Ribosomes contain both RNA and protein

Ribozymes are RNA-based enzymes capable of RNA cleavage

• RNA molecules may be the precursors to life as they can both

• Form complementary base pairs and replicate (like DNA)

• Perform enzymatic functions (like proteins)

Genes

Genes are not just “beads on a string” – they have complex structure

Gene structure• Genes are fragmented, containing non-protein-coding

introns between the functional exons

• On average ~2000-3000 bp coding, but there can be >10,000 bp between exons

• Size can vary by up to 4 orders of magnitude

Mutation

• DNA mutation is any change in DNA sequence

• Mutation can occur due to:

• DNA damage from environmental or chemical agents (eg. UV)

• Genetic events (eg. recombination - exchange of DNA between chromosomal segments)

Base level mutation

Changes that affect a single nucleotide:

• UV light can produce thymidine dimers which can cause deletions of a single base pair during replication

• Repeated sequences can cause insertions and deletions

• Methylated Cs can deaminate to Ts

Gene level mutation

• Tandem gene duplication can result from unequal DNA exchange between chromosomes (unequal crossover)

Changes that affect an entire gene:

Chromosome level mutation

Deletion

Translocation

Inversion

Copy number changes

Changes that affect part of a chromosome:

Role of mutation in disease

Mutation always has the potential to cause disease:

Single amino acid change in hemoglobin causes

sickle cell anemia

Cancer occurs when mutations cause cells to grow

in an uncontrolled way

Down syndrome is caused by a third copy

of chromosome 21

Role of mutation in evolutionMutation is not all bad!

• Occurs at a high rate in all our cells and does NOT always have negative effects

• No mutation

population cannot change and adapt to new conditions

• Random changes in DNA sequence

beneficial changes in phenotype

natural selection

evolution of population

Beneficial mutations

Changes in DNA sequence can be beneficial:

• Duplication of a gene allows one copy to mutate freely, which can result in a new and different gene

B

• Some changes in DNA sequence of molecules that recognize bacteria can protect against disease

Human Genome Project

Aim:

Determine the entire sequence of the human genome.

3 billion base pairs

Problem:

It’s really big!

What does the sequence mean?TCACAATTTAGACATCTAGTCTTCCACTTAAGCATATTTAGATTGTTTCCAGTTTTCAGCTTTTATGACTAAATCTTCTAAAATTGTTTTTCCCTAAATGTATATTTTAATTTGTCTCAGGAGTAGAATTTCTGAGTCATAAAGCGGTCATATGTATAAATTTTAGGTGCCTCATAGCTCTTCAAATAGTCATCCCATTTTATACATCCAGGCAATATATGAGAGTTCTTGGTGCTCCACATCTTAGCTAGGATTTGATGTCAACCAGTCTCTTTAATTTAGATATTCTAGTACATACAAAATAATACCTCAGTGTAACCTCTGTTTGTATTTCCCTTGATTAACTGATGCTGAGCACATCTTCATGTGCTTATTGACCATTAATTAGTCTTATTTGTTAAATGTCTCAAATATTTTATACAGTTTTACATTGTGTTATTCATTTTTTAAAAAATTCATTTTAGGTTATATGTATGTGTGTGTCAAAGTGTGTGTACATCTATTTGATATATGTATGTCTATATATTCTGGATACCATCTCTGTTTCATGCATTGCATATATATTTGCCTATTTAGTGGTTTATCTTTTCATTTTCTTTTGGTATCTTTTCATTAGAAATGTTATTTATTTTGAGTAAGTAACATTTAATATATTCTGTAACATTTAATGAATCATTTTATGTTATGTTTAGTATTAAATTTCTGAAAACATTCTATGTATTCTACTAGAATTGTCATAATTTTATCTTTTATATACATTGATATTTTTATGTCAAATATGTAGGTATGTGATATTATGCACATGGTTTTAATTCAGTTAATTGTTCTTCCAGATGTTTGTACCATTCCAACATCATTTAAATCATTAAATGAAAAGCCTTTCCTTACTAGCTAGCCAGCTTTGAAAATCCATTCATAGGGTTTGTGTTAATATATTTTTGTTCTTTTTTTTCCTTTCTACTGATCTCTTTATATTAATACCTACTGTGGCTTTATATGAAGTCATGGAATAATACGTAGTAAGCCCTCTAACACTGTTCTGTTACTGTTGTTATTGTTTTCTCAGGGTACTTTGAAATATTCGAGATTTTATTATTTTTTAGTAGCCTAGATTTCAAGATTGTTTTGACGATCAATTTTTGAATCAATTGTCAATATTTTTAGTAATAAAATGATGATTTTTGATTGGAAATACATTAAATCTATAAGCCAAATTGGAGATTATTGATATATTAACAAAAATGAGTTTTCCAGTCCATGAATGTATGCACATTATAAAATTCATTCTTAAGTATGTCATTTTTTAAGTTTTAGTTTCAGCAGTATATGTTTGTTACATAGGTAAACTCCTGTCATGGGGGTTAGTTGTACAGGTTATTTTATCATCCAGGCATAAAGCCCAGTACCCAGTAGTTATCTTTTCTGCTCCTCTCCCTCCTGTCACCCTCCACTCTCAAGTAGACCCCAGTTTCTGTTGTTCTCTTCTTTGCATTAATGACTTCTCATCATTTAGATTGCACTTGTAAGTGAGAACAGGACGTATGTGGTTTTCTACTCCTGTGTTAGTTTGCTAAGGATAACCACCTCCATCTCCATCCATGTTCCCACAAAAGACATGATCTCCTTTTTTATGGCTGCATATTATTCCATGGTATATATGTACCACATTTTCTTTATCCAATCTGTCATTGATGGACATTTAGGTTGTTTCCACATCATTGCCGTTGTAAATACTGCTGCAGTGAATATTCGTGTGTATGTCTTTATGGTAGAATGATTTATATTCCTCTGGGTATATTTCCAAGTAATGGGATGGTTGGGTCAAATGGTAATTCTGCTTTTAGCTTTTTGAGGAATTGCCATATTGCCTTTCACAACGGTTGAACTAATTTATACTCCCAAGAGTGTATAAGTTGTTCCTTTTTCTCTGCAACCTCGACATCACCTGTTATTTATGACTTTTATATAATAGCCATTCTGCTGGTCTGAGATGGTATCTCATTATGATTTTGATTTGCATTTCTCTAATGCTCAGTGATATTGAGCTTGGCTGCATATATGTCTTCTTTTAAAAATATCTGTTCATGTCCTTTGCCTAATTTATAACGGGGTTGTTTGTTTTTCTCTTGTAAATTTGTTTAAGTTCCTTATAGATTCTAGGTATTAAACCTTTTTTCAGAGGCGTGGCTTGCAAATATTTTCTCCCATTCTATAGGTTGTCTGTTTATTCTGTTGATAGTTTCCCTTGCTGTGCAGAAGCTCTTAACTTTAATTAGATCCGACTTGTCAATTTTTGCTTTGGTCGCAATTGCTTTTGATGTTATTGTCGTGAAATCTTTGCTAGTTCTTAGGTCCAGGATGATATTGCCCAAGTTGTCTTCCAGGGCTTTTATAATTTTGGATTTTACATTTAAGTCTTAATATATTTATTAAATTTGTTAGGGTTTCAGGATACAAGGACAATATAGCAGCAAACAATGTAAAAGTAAAATCTGAAAAATAATAGAAAACAGTTTAATTGAACACTTTACCATTATGTAATGCCCTTCTTTGTCTTTCCTGATCTTTGTTGGTTTGAAGTTCAAAAAAGACAAACTTAATGGTACAATAGGTATTGTAGATTTCAGGACTTTCTGTATAAAATATTTTGTATATATGAATAGATCATTTTTTATTTCCAGTCTTTAAACATTTTCTTAACATTTTCTTCTATTGCTTCACTTCACTCGCTAGGACCATCAGGACAGTGTTGAACAGAAATTGTCAGACTGATCATCACAACTTTTTCTAGATTTTAGAAGGAAATTTTTCTTTATTTCAACATAAAGCAGCATGTTAATGCCAAGTTTTAATATGTGTTATCAGATTGAAATTTTTTTGTATATTTCTACATTACCAAGAATTTTTAGCAAGAGTTTTTGTTGAGTTTTAATTTAAAAATCATTTGTTAATTTCATCTGATTTTTTTATTTCTCTTTTTACCTTAAGAGATTAAACTGACTACAGATTGAATATAAACAAACAAACAAACAAACAAAAACTCTAAAATGCTGTGGATCAACACCACTTAGTAATTTGTATACTTGGATTCAATTTGCTGAAATTTTGTTAGACATTTTTGCGTCGATATTTATGAGGGATGTTGATCTGTAAAAGTATTAAAATGCCTTTGACAGATTTTGATAGCAGTGTTATTCTGGCCTAATAAATCAAACTGAGGTATGATCCTTCCTTTTCTATTTCTTAATAGCATTTTTAAAATTGGTGGTTTTTTCCTTCCTTAGTGAAATTTACCAGCAAAGTAACAGGCCTTATATTTCTCTTGTGGAAATATTTTAATTTCAAATTAATGGTATTTTGTTCTTGTAGGGTGGTAATTTTCTCTGTGTTTGGTCTTAATGGACTCTTAGCTGATCACCCAGTTACTCAGCGAGGTCTCTTCACTCTGGAAGAGCTGGAACTCCAGTGTGTTTTAGTGCAGCATGACCACGGGTATTACCGTTCAACATTTAGGCTTTATCAGTGATAACTATTTGTCCTCATGGAGTTTTTGCCGCTGGGCCTACACAGTTTAGGCTTCAGCTTAGAACACATAATGAATTCTTATGCAGATTTCTGCCCACCTTTGACCTTTCATGATTTCCTCTTCTTGGGTAAGCTGCCTTATTAATCTGATACACTTCAGCAGTCCAGAACTACACTCTTTCCCTTCTCTGCTCTTGGAGATGACTCTTTTGTCTGAGATTCACTTTGCTGTGCTGAAAAAGAAAAGTGCTTCAAGGAAGATACCAAGGAAAATCACAGGGCTCATTTATGTATTTCTCTTCTTTCAAGGACTACAGCTTTGTGTTGCCTATGTTCAATTTCTGAAAATAATTAGAGCATATATACTCTGTGTGAGAAGGCAAATCCAGACAGTTAGTTTGTATGACTAGAAGCAGAAGTCTACATGGAGAATTTTACTTAACTGTGTTATAGTTTCTTTAATTATTTCAAGAGTATGTTTAATGTTCCACAGATCTCATTCTATAAATCTTTATCATCTTAGAGCTCTGATACTATTTAGAATTACTATTCCTTCAAATAAGAGATTAGAAACAGGGTTATATTTGGGGTAGGTTGACTTACTTTTCTGGGAACCAAAGCATATTAAATTGACCAGTTTTAACACACTTCTATGTATGCACAAAGATATATATTTACATTCTGCAAAATCATTCTTTCCTTTTTGAATTTGAAAAGGATCTTTGGTATACAGATATTCAATAGCCAGCCTGAAGATTCATTTGAATTCATTTAATGTTTAGATTCACTACATGAAATGATCCAGAAGAGAGTACTCAAATATAAGTATCTATAACGATGGAAATATACATCTCCACTGCCCAAGATGGTAGTCATGAGTCAATATTGATCATGTGAGACGTGGCAAGTGTTACTCAGGGTCTCAATATTTAAATGTATTAAGCTTTAATTAATGTAAATTTGAATTTAGCAAAACATGTATAGCTTGTGGTTACTGTTTTATTCAGTGCCAATATAGAACATTTCCATGATTACAGAAAGTTATCTTAGAATACTCAGTTCTGGACTATTTTATCTGGCTAAATTAAATGTTAAAATATTACAAATTCATCTTCAGGCTGGCTGTTGAATATTTTTATAGCAAAAGTCATTTATAAATTTAAAACTCAAATAATTATCTTTTTCAATATGTAAAATATGTCTTTACATATTCTACTCCCTTCTTACATACATATTCTGATGTAACATAGGTATTCTCTTATTCATGCACACTGAAATGACAACATAAATAATTTTACTAAGTGTCACCATATAAAAAACTTTGAACAAAATCAGATTATATCACTGTGGATATTTCTATTTTGAACTAACTTAGATGATAATTTTAATCTATATCCTAGATGAACTTTAAATCAATAAAATCTCTCAATGGTGTTATAAATCTCAAGCCATTAGCCACTGATTATCCCATTTTTATTCTTTTCATATTAATTTTATTGCCATGTATGAATGCTGTAGCATCCATGTTTAAATACTAGTTAACAAAATGCACTGGCATCAGATACAATAAGGATGAAATGAGATATAATTAGGACTCTGGTAACACACATAAAATTGGAAAGATACCCTGAAATTCAAGCCAAGAAGATATTTATCCAGCTTATTTTATTTTGAGACAGAGTCTTGCTCTCTCACTCAGGCTGGAGTGCAGTGGACCATTCTAGGCTCGCTCCAACCTCTGTCTCCCAAATTGAAGTAATTCTCGTGCCTCAATCTCCCGAGTAGCTGGGATTACAGGCATGTGTCACCAAGCCTGGCTGATTTTTGTAGTTTTAGTAGAGACGGGGTTTCACCATGATGGCCAGGCTGGTCTTGAACTCCTGGCCTCAAGTGACTGGAACACCTCGGCCTCCTAAAGTGCTGGGATTACAGACGAGAGCCACTGAACAGCTTTGATCCAACTTATTTGGATGAATGAGTTACATATTTTACATTAAATCTGTTATTGTGATAATTCTTCATGTTATTTTCCATGTATAGATTTATATATAATGTAATTTTAATTTTTTTTCACCGGAGAGTATAAACAACAATTATTTTATAAACAGGATAATAAAAATAAGACAAAAATTGTTGAAATGTCTTCATTTGACTACTAACTTTTTACATGTTTGTTACTTTGAAGCTGTTATCAATACTTGTGATGTATTACAATTAAGTAAAGATTTAAAGATGCCATTTTTAACTTATTATGACACAAAGTCTATAAATTCTTATATTTTGAGATTTGTATTTAAATAACTTGTGAAATTTAATTTTAAAATAAAATTTCTTCTATGGATTGGTCTTCAATCGAGGCATAAAAAGGAATATAACAGTGTGGCACTATAACTTCTATATTGAATTTCTATATTATTTAACACAATTATAATTTTGCTAATGAATTGTAATGTTTTTAAAAAGCTAGGTGAATTTTATTAAATTCATTACATGGCGATAACACAGAGAAAACATTTTGGGGATTCTTTTAAAATGGTATGTACAAAAGCTTAAAAGTTGTTATGTAGTGGCAGAGATAAAAAAGTAAAACAAAAAAAAGCTTAAAAGTTTGCTTTACTATTTATAGGCTCATAAGTGTAAGTGTGCCAGAAAATGAAAAAGAAAGGAGAGAAATTATAAATAACTGTGTGGAAAACACAGATAAAGCATAAAGATAGAATATAAAGATAGAAGCATTTTAATATGAGGCAGTGATGGCTTTTTGAAGAATCCCAACTAAGGACCTACTTTTAGTTAATAAATAATATGTTTCTAATCCCTATATTGTCCACAGCAACCTTTTTAGGACATGGAGCAGTGACTATGAGTGCCAGAAGGCAAGAGTAGAAGCAATTGTAAAATCATGAACACTAGTTTGTAAAATCCTCACTGAGATATAATATCTGTTTGCCTCTACCTTAGAATTATTAATGTCTTGAGGGCTGGGA

A very small piece of chromosome 21

Model organisms

Phil Hieter

Sequenced / in progress:

THANK YOU