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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
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•
•
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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
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–
–
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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 is the study of genes”
-- Griffiths et al, Introduction to Genetic Analysis
Genetics – study of single or a few gene and their
phenotypic effect
Genomics – a study of all the genes in the genome and
their interaction
DNA microarray analysis of tumor
What is a gene?
“A gene is a section of a threadlike double helical molecule
called DNA”
-- Griffiths et al, Introduction to Genetic Analysis
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
Inheritance
Pea flowers can be
purple or white
Cross purple and white
- get all purple
Gregor Mendel
(1860s)
Cross offspring
- get ¾ purple
Inheritance occurs in a discrete manner
Mendelian inheritance
• There are 2 copies of each gene in each cell, and a single
gene determines a single trait
• Genes have alleles that are dominant or recessive
phenotype
genotype
AA
dominant allele
aa
Aa
recessive allele
Alleles reassort
randomly in offspring
AA A a A a a a
Polydactyly is a
dominant trait
Non-Mendelian inheritance
Some traits are determined by 2 or more genes, each with
multiple alleles
Continuous traits are
determined by large numbers
of genes
3 different genes determine
color and pattern in the
foxglove flower
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
Genes
Chromosomes
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
• Recessive alleles on the X will appear dominant in males
(no other allele present to mask the recessive phenotype)
Example: red-green color
blindness is X-linked
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
Inactive Xs condense to form
Barr bodies during development
Inactivation is random
during development
Barr bodies in female cells
Color pattern seen in female
calico cats due to random X
chromosome inactivation
DNA structure
• Only 4 nucleotides (bases)
make up all DNA:
A (adenine)
-T
C (cytosine)
-G
T (thymine)
-A
G (guanine)
-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
Replication
fork
• Each child strand has one
of the parent strands
• Replication only occurs in the
5’ to 3’ direction
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
• Methylated Cs can
deaminate to Ts
• Repeated sequences can
cause insertions and deletions
Gene level mutation
Changes that affect an entire gene:
• Tandem gene duplication can result from unequal DNA
exchange between chromosomes (unequal crossover)
Chromosome level mutation
Changes that affect part of a chromosome:
Deletion
Inversion
Translocation
Copy number
changes
Role of mutation in disease
Mutation always has the potential to cause disease:
Single amino acid change
in hemoglobin causes
sickle cell anemia
Down syndrome is
caused by a third copy
of chromosome 21
Cancer occurs when
mutations cause cells to grow
in an uncontrolled way
Role of mutation in evolution
Mutation 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:
• Some changes in DNA sequence of molecules that
recognize bacteria can protect against disease
• Duplication of a gene allows one copy to mutate freely,
which can result in a new and different gene
B
Human Genome Project
Aim:
Determine the entire sequence of the
human genome.
Problem:
It’s really big!
3 billion base pairs
What does the sequence mean?
TCACAATTTAGACATCTAGTCTTCCACTTAAGCATATTTAGATTGTTTCCAGTTTTCAGCTTTTATGACTAAATCTTCTAAAATTGTTTTTCCCTAAATGTATATTTTAATTTGTCTCAGGAGTAGAATTTCTGAGTCATAAAGCGGT
CATATGTATAAATTTTAGGTGCCTCATAGCTCTTCAAATAGTCATCCCATTTTATACATCCAGGCAATATATGAGAGTTCTTGGTGCTCCACATCTTAGCTAGGATTTGATGTCAACCAGTCTCTTTAATTTAGATATTCTAGTACAT
ACAAAATAATACCTCAGTGTAACCTCTGTTTGTATTTCCCTTGATTAACTGATGCTGAGCACATCTTCATGTGCTTATTGACCATTAATTAGTCTTATTTGTTAAATGTCTCAAATATTTTATACAGTTTTACATTGTGTTATTCATT
TTTTAAAAAATTCATTTTAGGTTATATGTATGTGTGTGTCAAAGTGTGTGTACATCTATTTGATATATGTATGTCTATATATTCTGGATACCATCTCTGTTTCATGCATTGCATATATATTTGCCTATTTAGTGGTTTATCTTTTCAT
TTTCTTTTGGTATCTTTTCATTAGAAATGTTATTTATTTTGAGTAAGTAACATTTAATATATTCTGTAACATTTAATGAATCATTTTATGTTATGTTTAGTATTAAATTTCTGAAAACATTCTATGTATTCTACTAGAATTGTCATAA
TTTTATCTTTTATATACATTGATATTTTTATGTCAAATATGTAGGTATGTGATATTATGCACATGGTTTTAATTCAGTTAATTGTTCTTCCAGATGTTTGTACCATTCCAACATCATTTAAATCATTAAATGAAAAGCCTTTCCTTAC
TAGCTAGCCAGCTTTGAAAATCCATTCATAGGGTTTGTGTTAATATATTTTTGTTCTTTTTTTTCCTTTCTACTGATCTCTTTATATTAATACCTACTGTGGCTTTATATGAAGTCATGGAATAATACGTAGTAAGCCCTCTAACACT
GTTCTGTTACTGTTGTTATTGTTTTCTCAGGGTACTTTGAAATATTCGAGATTTTATTATTTTTTAGTAGCCTAGATTTCAAGATTGTTTTGACGATCAATTTTTGAATCAATTGTCAATATTTTTAGTAATAAAATGATGATTTTTG
ATTGGAAATACATTAAATCTATAAGCCAAATTGGAGATTATTGATATATTAACAAAAATGAGTTTTCCAGTCCATGAATGTATGCACATTATAAAATTCATTCTTAAGTATGTCATTTTTTAAGTTTTAGTTTCAGCAGTATATGTTT
GTTACATAGGTAAACTCCTGTCATGGGGGTTAGTTGTACAGGTTATTTTATCATCCAGGCATAAAGCCCAGTACCCAGTAGTTATCTTTTCTGCTCCTCTCCCTCCTGTCACCCTCCACTCTCAAGTAGACCCCAGTTTCTGTTGTTC
TCTTCTTTGCATTAATGACTTCTCATCATTTAGATTGCACTTGTAAGTGAGAACAGGACGTATGTGGTTTTCTACTCCTGTGTTAGTTTGCTAAGGATAACCACCTCCATCTCCATCCATGTTCCCACAAAAGACATGATCTCCTTTT
TTATGGCTGCATATTATTCCATGGTATATATGTACCACATTTTCTTTATCCAATCTGTCATTGATGGACATTTAGGTTGTTTCCACATCATTGCCGTTGTAAATACTGCTGCAGTGAATATTCGTGTGTATGTCTTTATGGTAGAATG
ATTTATATTCCTCTGGGTATATTTCCAAGTAATGGGATGGTTGGGTCAAATGGTAATTCTGCTTTTAGCTTTTTGAGGAATTGCCATATTGCCTTTCACAACGGTTGAACTAATTTATACTCCCAAGAGTGTATAAGTTGTTCCTTTT
TCTCTGCAACCTCGACATCACCTGTTATTTATGACTTTTATATAATAGCCATTCTGCTGGTCTGAGATGGTATCTCATTATGATTTTGATTTGCATTTCTCTAATGCTCAGTGATATTGAGCTTGGCTGCATATATGTCTTCTTTTAA
AAATATCTGTTCATGTCCTTTGCCTAATTTATAACGGGGTTGTTTGTTTTTCTCTTGTAAATTTGTTTAAGTTCCTTATAGATTCTAGGTATTAAACCTTTTTTCAGAGGCGTGGCTTGCAAATATTTTCTCCCATTCTATAGGTTGT
CTGTTTATTCTGTTGATAGTTTCCCTTGCTGTGCAGAAGCTCTTAACTTTAATTAGATCCGACTTGTCAATTTTTGCTTTGGTCGCAATTGCTTTTGATGTTATTGTCGTGAAATCTTTGCTAGTTCTTAGGTCCAGGATGATATTGC
CCAAGTTGTCTTCCAGGGCTTTTATAATTTTGGATTTTACATTTAAGTCTTAATATATTTATTAAATTTGTTAGGGTTTCAGGATACAAGGACAATATAGCAGCAAACAATGTAAAAGTAAAATCTGAAAAATAATAGAAAACAGTTT
AATTGAACACTTTACCATTATGTAATGCCCTTCTTTGTCTTTCCTGATCTTTGTTGGTTTGAAGTTCAAAAAAGACAAACTTAATGGTACAATAGGTATTGTAGATTTCAGGACTTTCTGTATAAAATATTTTGTATATATGAATAGA
TCATTTTTTATTTCCAGTCTTTAAACATTTTCTTAACATTTTCTTCTATTGCTTCACTTCACTCGCTAGGACCATCAGGACAGTGTTGAACAGAAATTGTCAGACTGATCATCACAACTTTTTCTAGATTTTAGAAGGAAATTTTTCT
TTATTTCAACATAAAGCAGCATGTTAATGCCAAGTTTTAATATGTGTTATCAGATTGAAATTTTTTTGTATATTTCTACATTACCAAGAATTTTTAGCAAGAGTTTTTGTTGAGTTTTAATTTAAAAATCATTTGTTAATTTCATCTG
ATTTTTTTATTTCTCTTTTTACCTTAAGAGATTAAACTGACTACAGATTGAATATAAACAAACAAACAAACAAACAAAAACTCTAAAATGCTGTGGATCAACACCACTTAGTAATTTGTATACTTGGATTCAATTTGCTGAAATTTTG
TTAGACATTTTTGCGTCGATATTTATGAGGGATGTTGATCTGTAAAAGTATTAAAATGCCTTTGACAGATTTTGATAGCAGTGTTATTCTGGCCTAATAAATCAAACTGAGGTATGATCCTTCCTTTTCTATTTCTTAATAGCATTTT
TAAAATTGGTGGTTTTTTCCTTCCTTAGTGAAATTTACCAGCAAAGTAACAGGCCTTATATTTCTCTTGTGGAAATATTTTAATTTCAAATTAATGGTATTTTGTTCTTGTAGGGTGGTAATTTTCTCTGTGTTTGGTCTTAATGGAC
TCTTAGCTGATCACCCAGTTACTCAGCGAGGTCTCTTCACTCTGGAAGAGCTGGAACTCCAGTGTGTTTTAGTGCAGCATGACCACGGGTATTACCGTTCAACATTTAGGCTTTATCAGTGATAACTATTTGTCCTCATGGAGTTTTT
GCCGCTGGGCCTACACAGTTTAGGCTTCAGCTTAGAACACATAATGAATTCTTATGCAGATTTCTGCCCACCTTTGACCTTTCATGATTTCCTCTTCTTGGGTAAGCTGCCTTATTAATCTGATACACTTCAGCAGTCCAGAACTACA
CTCTTTCCCTTCTCTGCTCTTGGAGATGACTCTTTTGTCTGAGATTCACTTTGCTGTGCTGAAAAAGAAAAGTGCTTCAAGGAAGATACCAAGGAAAATCACAGGGCTCATTTATGTATTTCTCTTCTTTCAAGGACTACAGCTTTGT
GTTGCCTATGTTCAATTTCTGAAAATAATTAGAGCATATATACTCTGTGTGAGAAGGCAAATCCAGACAGTTAGTTTGTATGACTAGAAGCAGAAGTCTACATGGAGAATTTTACTTAACTGTGTTATAGTTTCTTTAATTATTTCAA
GAGTATGTTTAATGTTCCACAGATCTCATTCTATAAATCTTTATCATCTTAGAGCTCTGATACTATTTAGAATTACTATTCCTTCAAATAAGAGATTAGAAACAGGGTTATATTTGGGGTAGGTTGACTTACTTTTCTGGGAACCAAA
GCATATTAAATTGACCAGTTTTAACACACTTCTATGTATGCACAAAGATATATATTTACATTCTGCAAAATCATTCTTTCCTTTTTGAATTTGAAAAGGATCTTTGGTATACAGATATTCAATAGCCAGCCTGAAGATTCATTTGAAT
TCATTTAATGTTTAGATTCACTACATGAAATGATCCAGAAGAGAGTACTCAAATATAAGTATCTATAACGATGGAAATATACATCTCCACTGCCCAAGATGGTAGTCATGAGTCAATATTGATCATGTGAGACGTGGCAAGTGTTACT
CAGGGTCTCAATATTTAAATGTATTAAGCTTTAATTAATGTAAATTTGAATTTAGCAAAACATGTATAGCTTGTGGTTACTGTTTTATTCAGTGCCAATATAGAACATTTCCATGATTACAGAAAGTTATCTTAGAATACTCAGTTCT
GGACTATTTTATCTGGCTAAATTAAATGTTAAAATATTACAAATTCATCTTCAGGCTGGCTGTTGAATATTTTTATAGCAAAAGTCATTTATAAATTTAAAACTCAAATAATTATCTTTTTCAATATGTAAAATATGTCTTTACATAT
TCTACTCCCTTCTTACATACATATTCTGATGTAACATAGGTATTCTCTTATTCATGCACACTGAAATGACAACATAAATAATTTTACTAAGTGTCACCATATAAAAAACTTTGAACAAAATCAGATTATATCACTGTGGATATTTCTA
TTTTGAACTAACTTAGATGATAATTTTAATCTATATCCTAGATGAACTTTAAATCAATAAAATCTCTCAATGGTGTTATAAATCTCAAGCCATTAGCCACTGATTATCCCATTTTTATTCTTTTCATATTAATTTTATTGCCATGTAT
GAATGCTGTAGCATCCATGTTTAAATACTAGTTAACAAAATGCACTGGCATCAGATACAATAAGGATGAAATGAGATATAATTAGGACTCTGGTAACACACATAAAATTGGAAAGATACCCTGAAATTCAAGCCAAGAAGATATTTAT
CCAGCTTATTTTATTTTGAGACAGAGTCTTGCTCTCTCACTCAGGCTGGAGTGCAGTGGACCATTCTAGGCTCGCTCCAACCTCTGTCTCCCAAATTGAAGTAATTCTCGTGCCTCAATCTCCCGAGTAGCTGGGATTACAGGCATGT
GTCACCAAGCCTGGCTGATTTTTGTAGTTTTAGTAGAGACGGGGTTTCACCATGATGGCCAGGCTGGTCTTGAACTCCTGGCCTCAAGTGACTGGAACACCTCGGCCTCCTAAAGTGCTGGGATTACAGACGAGAGCCACTGAACAGC
TTTGATCCAACTTATTTGGATGAATGAGTTACATATTTTACATTAAATCTGTTATTGTGATAATTCTTCATGTTATTTTCCATGTATAGATTTATATATAATGTAATTTTAATTTTTTTTCACCGGAGAGTATAAACAACAATTATTT
TATAAACAGGATAATAAAAATAAGACAAAAATTGTTGAAATGTCTTCATTTGACTACTAACTTTTTACATGTTTGTTACTTTGAAGCTGTTATCAATACTTGTGATGTATTACAATTAAGTAAAGATTTAAAGATGCCATTTTTAACT
TATTATGACACAAAGTCTATAAATTCTTATATTTTGAGATTTGTATTTAAATAACTTGTGAAATTTAATTTTAAAATAAAATTTCTTCTATGGATTGGTCTTCAATCGAGGCATAAAAAGGAATATAACAGTGTGGCACTATAACTTC
TATATTGAATTTCTATATTATTTAACACAATTATAATTTTGCTAATGAATTGTAATGTTTTTAAAAAGCTAGGTGAATTTTATTAAATTCATTACATGGCGATAACACAGAGAAAACATTTTGGGGATTCTTTTAAAATGGTATGTAC
AAAAGCTTAAAAGTTGTTATGTAGTGGCAGAGATAAAAAAGTAAAACAAAAAAAAGCTTAAAAGTTTGCTTTACTATTTATAGGCTCATAAGTGTAAGTGTGCCAGAAAATGAAAAAGAAAGGAGAGAAATTATAAATAACTGTGTGG
AAAACACAGATAAAGCATAAAGATAGAATATAAAGATAGAAGCATTTTAATATGAGGCAGTGATGGCTTTTTGAAGAATCCCAACTAAGGACCTACTTTTAGTTAATAAATAATATGTTTCTAATCCCTATATTGTCCACAGCAACCT
TTTTAGGACATGGAGCAGTGACTATGAGTGCCAGAAGGCAAGAGTAGAAGCAATTGTAAAATCATGAACACTAGTTTGTAAAATCCTCACTGAGATATAATATCTGTTTGCCTCTACCTTAGAATTATTAATGTCTTGAGGGCTGGGA
A very small piece of chromosome 21
Model organisms
Sequenced / in progress:
Phil Hieter
THANK YOU