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