Download Genetic Variation: Overview

Genetic Variation: Overview
Jay Taylor
Jay Taylor (ASU)
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Motivation
Population genetics is the study of genetic variation
Estimated frequency of the medionigra morph
in the Cothill scarlet tiger moth population
0.12
0.1
frequency
0.08
0.06
0.04
0.02
0
1935
1940
1945
1950
1955
1960
1965
1970
1975
1980
year
sources: Fisher & Ford (1947), O’Hara (2005)
Jay Taylor (ASU)
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Motivation
We can study polymorphism within populations ...
Nair et al. (2003): A selective sweep driven by pyrimethamine treatment in southeast asian
malaria parasites.
Jay Taylor (ASU)
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Motivation
... as well as divergence between populations.
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Motivation
Genetic variation is affected by several interacting processes
Mutation and recombination tend to increase variation by creating new
genotypes and sometimes re-creating old genotypes that have been lost.
Migration can increase local levels of variation.
Natural selection alters the genetic composition of populations and can either
reduce or increase variation depending on its mode of action.
Purifying selection tends to reduce variation.
In some cases, balancing selection and diversifying selection can act to
maintain variation.
Demographic stochasticity (genetic drift) tends to reduce genetic variation
through the random loss of rare alleles.
Predicting how these processes will influence genetic variation can be difficult, especially
when several processes act in the same population. For this reason, we often use
mathematical models to generate hypotheses that can be tested with sequence data.
Jay Taylor (ASU)
APM 504
Jan 13, 2015
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Motivation
Evolution by Natural Selection
In 1859, Charles Darwin and Alfred Russell Wallace proposed that natural selection
could explain how populations become adapted to their environments.
Variation within populations - individuals have different traits (phenotypes).
height and weight are approximately normally distributed
variation for susceptibility to HIV-1 infection and progression to AIDS
Selection - traits influence fecundity and survivorship (fitness).
larger body size may be beneficial in cold environments
height may influence mating success (sexual selection)
Heritability - offspring are similar to their parents.
variation has both environmental and heritable components
differences in height are partly heritable, but are also influenced by
childhood nutritition
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Motivation
Example: Beak size in the Medium Ground Finch (Geospiza fortis)
Restricted to the Galapagos Islands.
Forages mainly on seeds.
Large seeds are handled more efficiently by birds with larger bills.
Large seeds predominate following drought years (e.g., 1977).
Jay Taylor (ASU)
APM 504
Jan 13, 2015
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Motivation
The most serious flaw in Darwin’s theory was his model of heredity, which was
based on:
blending inheritance - offspring traits are averages of parental traits.
This is problematic because it leads to a loss of variation.
Ironically, in 1866, Gregor Mendel proposed a particulate model of inheritance:
Traits are determined by genes.
Each gene can have finitely-many different types called alleles.
Different alleles may produce different traits.
Offspring are similar to their parents because they inherit parental alleles.
Mendel was essentially correct, but his work was largely ignored until it was rediscovered
by Hugo de Vries and Carl Correns in 1900.
Jay Taylor (ASU)
APM 504
Jan 13, 2015
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Motivation
Population Genetics and the Modern Synthesis
A coherent theory explaining how natural selection could operate in the context of
Mendelian genetics did not appear until the 1930’s with the development of theoretical
population genetics (R. A. Fisher, S. Wright, J. B. S. Haldane).
Genes are physical entities carried on chromosomes.
Heritable variation is produced by mutation and recombination.
Selection causes changes in the frequencies of genotypes that in turn affect traits
that influence fitness.
Population genetics can explain both microevolutionary and macroevolutionary
changes.
Population genetics focuses on understanding evolution at the molecular level: how
does natural selection affect the dynamics of gene frequencies?
Jay Taylor (ASU)
APM 504
Jan 13, 2015
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Motivation
Many fundamental problems in evolutionary biology involve population genetics:
Neutrality vs. selection: how much of the genome is under selection?
Genetics of adaptation: Does adaptation rely mainly on standing variation or on
new mutations?
How do demography and life history influence the rate of adaptation?
Genome evolution: gene duplication, evolution of gene regulatory networks
Evolution of sex and recombination
Speciation genetics and biodiversity
Jay Taylor (ASU)
APM 504
Jan 13, 2015
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Motivation
Population genetics is also used to study problems in ecology and anthropology
Atkinson et al. (2008): mtDNA Variation Predicts Population Size in Humans
Jay Taylor (ASU)
APM 504
Jan 13, 2015
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Motivation
Pathogen genealogies provide insight into epidemiological processes
Grenfell et al. (2004): Unifying the Epidemiological and Evolutionary Dynamics of Pathogens
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APM 504
Jan 13, 2015
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Molecular Genetics
The Central Dogma of Molecular Biology
Jay Taylor (ASU)
APM 504
Jan 13, 2015
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Molecular Genetics
DNA and RNA are polymers of nucleotides
Nucleotides have three components:
a 5-carbon sugar: deoxyribose (DNA)
or ribose (RNA)
a phosphate group linked to the
5’ carbon of the sugar
a nitrogenous base linked to
the 1’ carbon of the sugar
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APM 504
Jan 13, 2015
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Molecular Genetics
Nucleic Acid Sugars
Deoxyribose contains one less hydroxyl (-OH) group than ribose.
The carbons are numbered clockwise 1’-5’.
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Molecular Genetics
Five Nitrogenous Bases
A, T, C, G in DNA
A, U, C, G in RNA
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Molecular Genetics
Nucleotides polymerize by forming phosphodiester
bonds
Nucleic acids are oriented and by convention
sequences are always written 5’ to 3’. Thus,
ATTGCA 6= ACGTTA.
Polymerization proceeds 5’ to 3’: RNA and DNA
molecules grow by adding new nucleotides at the 3’
end.
The addition of new nucleotides is catalyzed by a
polymerase.
Nucleotides can be removed by nucleases.
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Molecular Genetics
Pyrimidine-purine base pairs form by hydrogen bonding
A-T and G-C base pairs form in DNA
A-T is replaced by A-U in RNA
A-T and G-C base pairs have similar
dimensions (∼ 2 nm).
G-C base pairs have three H-bonds and are
more stable than A-T base pairs.
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Jan 13, 2015
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Molecular Genetics
Base pairing allows complementary strands to hybridize
Hybridization occurs spontaneously
between complementary ssDNA under
physiological conditions.
Strands are anti-parallel, e.g., ATTGCA is
complementary to TGCAAT.
Hybridized strands ‘melt’ (disassociate) at
high temperatures.
Key to replication and transcription of
DNA and to many technologies: PCR,
microarrays.
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Molecular Genetics
DNA replication is semiconservative
Each copy contains one of the original strands and one new strand.
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Molecular Genetics
The Central Dogma of Molecular Biology
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Molecular Genetics
Proteins are polymers formed from 20 standard amino acids
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Molecular Genetics
The amino acid sequence determines both the structure and function of a protein
HIV-1 RT
Jay Taylor (ASU)
human hemoglobin
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Molecular Genetics
The Genetic Code is Degenerate
20 amino acids
4 nucleotides
43 = 64 codons
1 start codon (AUG)
3 stop codons
third position is often
degenerate
synonymous vs.
nonsynonymous mutations
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Jan 13, 2015
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Molecular Genetics
The Human Karyotype
Most human cells are diploid
with 23 pairs of chromosomes.
22 pairs of autosomes
X, Y sex chromosomes
Exceptions: gametes are haploid and
have 23 chromosomes; red blood
cells lack nuclei altogether.
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Molecular Genetics
Contents of the Human Genome
3 billion base pairs per haploid
complement
23,000 protein-coding genes: exons
(2%), introns (24%)
transposable elements (51%) can
move around the genome and many
can replicate
satellite DNA (6%) consists of
non-coding tandem repeats
Rollins et al. (Genome Research, 2006)
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Molecular Genetics
Mitochondria also have genomes
Human mitochondrial genome:
circular
16569 bp
13 protein-coding genes
12S and 16S rRNA genes
22 tRNA genes
maternally-inherited
Mitochondria are sub-cellular organelles that produce chemical energy (ATP). Human
cells contain from ten to several thousand mitochondria per cell.
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Mendelian Genetics
Mitosis, Meiosis and Mendelian Genetics
Eukaryotic cells can divide by two processes: mitosis and meiosis.
Mitosis is the process by which diploid somatic cells divide in two. Apart from
mutation, the daughter cells are genetically identical to the parent.
Meiosis is the process by which diploid germ cells produce haploid gametes
(eggs, sperm). This involves two rounds of cell division and results in the
production of four gametes.
Mendelian genetics (Mendel, 1866) explains how offspring inherit genomes and
traits from their parents.
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Mendelian Genetics
Mendel’s Law of Segregation
A locus is a position in a genome.
A diploid cell carries two copies of each
locus called alleles.
Homozygotes have two identical alleles
(PP, pp); heterozygotes have two different
alleles (Pp).
Each parent transmits just one of these
two alleles to each gamete.
It is usually the case that both copies are
equally likely to be transmitted to the
gametes.
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Mendelian Genetics
Mendel’s Law of Independent Assortment
Each pair of homologous chromosomes
segregates independently of the others.
Loci on the same chromosome are
usually inherited together, but can be
reshuffled by recombination.
Both inter- and intra-chromosomal
recombination are a source of genetic
variation.
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Mendelian Genetics
Crossing over during meiosis I produces recombinant gametes.
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Mendelian Genetics
Recombination Rates
Recombination (usually) occurs only between homologous chromosomes.
Each pair of homologs undergoes at least one crossover during meiosis, but
multiple crossovers can also occur.
The probability that two loci recombine is an increasing function of the physical
distance (number of base pairs) between them.
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Mendelian Genetics
Non-recombining Markers
The mitochondrion is maternally inherited and
so its genome does not recombine.
Most of the Y chromosome is non-recombining, except for
two short terminal regions that recombine with the X
(pseudo-autosomal regions).
Recombination occurs along the entire length
of the X chromosome in females.
Non-recombining loci share the same genealogy, e.g., the
entire mtDNA genome has a single genealogical history.
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Mendelian Genetics
References
Alberts, B. et al. (2007) Molecular Biology of the Cell. 5’th edition. Garland
Science.
Krebs, J. E., Goldstein, E. S. and Kilpatrick, S. T. (2011) Lewin’s Genes X. Jones
and Bartlett.
Sturtevant, A. H. and Lewis, E. B. (2001) A History of Genetics. Cold Spring
Harbor Laboratory.
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