genetic variation: overview · traits are determined by genes. each gene can have nitely-many di...

Genetic Variation: Overview

Jay Taylor

Jay Taylor (ASU) APM 504 Jan 13, 2015 1 / 34

Motivation

Population genetics is the study of genetic variation

Estimated frequency of the medionigra morph in the Cothill scarlet tiger moth population

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0.02

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0.06

0.08

0.1

0.12

1935 1940 1945 1950 1955 1960 1965 1970 1975 1980

year

freq

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sources: Fisher & Ford (1947), O’Hara (2005)


Motivation

We can study polymorphism within populations ...

Nair et al. (2003): A selective sweep driven by pyrimethamine treatment in southeast asianmalaria parasites.


Motivation

... as well as divergence between populations.


Motivation

Genetic variation is affected by several interacting processes

Mutation and recombination tend to increase variation by creating newgenotypes 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 tomaintain variation.

Demographic stochasticity (genetic drift) tends to reduce genetic variationthrough the random loss of rare alleles.

Predicting how these processes will influence genetic variation can be difficult, especiallywhen several processes act in the same population. For this reason, we often usemathematical models to generate hypotheses that can be tested with sequence data.


Motivation

Evolution by Natural Selection

In 1859, Charles Darwin and Alfred Russell Wallace proposed that natural selectioncould explain how populations become adapted to their environments.

Variation within populations - individuals have different traits (phenotypes).

height and weight are approximately normally distributedvariation 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 environmentsheight may influence mating success (sexual selection)

Heritability - offspring are similar to their parents.

variation has both environmental and heritable componentsdifferences in height are partly heritable, but are also influenced bychildhood nutritition


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).


Motivation

The most serious flaw in Darwin’s theory was his model of heredity, which wasbased 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 rediscoveredby Hugo de Vries and Carl Correns in 1900.


Motivation

Population Genetics and the Modern Synthesis

A coherent theory explaining how natural selection could operate in the context ofMendelian genetics did not appear until the 1930’s with the development of theoreticalpopulation 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 traitsthat influence fitness.

Population genetics can explain both microevolutionary and macroevolutionarychanges.

Population genetics focuses on understanding evolution at the molecular level: howdoes natural selection affect the dynamics of gene frequencies?


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 onnew 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


Motivation

Population genetics is also used to study problems in ecology and anthropology

Atkinson et al. (2008): mtDNA Variation Predicts Population Size in Humans


Motivation

Pathogen genealogies provide insight into epidemiological processes

Grenfell et al. (2004): Unifying the Epidemiological and Evolutionary Dynamics of Pathogens


Molecular Genetics

The Central Dogma of Molecular Biology


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 the5’ carbon of the sugar

a nitrogenous base linked tothe 1’ carbon of the sugar


Molecular Genetics

Nucleic Acid Sugars

Deoxyribose contains one less hydroxyl (-OH) group than ribose.

The carbons are numbered clockwise 1’-5’.


Molecular Genetics

Five Nitrogenous Bases

A, T, C, G in DNA

A, U, C, G in RNA


Molecular Genetics

Nucleotides polymerize by forming phosphodiesterbonds

Nucleic acids are oriented and by conventionsequences are always written 5’ to 3’. Thus,ATTGCA 6= ACGTTA.

Polymerization proceeds 5’ to 3’: RNA and DNAmolecules grow by adding new nucleotides at the 3’end.

The addition of new nucleotides is catalyzed by apolymerase.

Nucleotides can be removed by nucleases.


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 similardimensions (∼ 2 nm).

G-C base pairs have three H-bonds and aremore stable than A-T base pairs.


Molecular Genetics

Base pairing allows complementary strands to hybridize

Hybridization occurs spontaneouslybetween complementary ssDNA underphysiological conditions.

Strands are anti-parallel, e.g., ATTGCA iscomplementary to TGCAAT.

Hybridized strands ‘melt’ (disassociate) athigh temperatures.

Key to replication and transcription ofDNA and to many technologies: PCR,microarrays.


Molecular Genetics

DNA replication is semiconservative

Each copy contains one of the original strands and one new strand.


Molecular Genetics

The Central Dogma of Molecular Biology


Molecular Genetics

Proteins are polymers formed from 20 standard amino acids


Molecular Genetics

The amino acid sequence determines both the structure and function of a protein

HIV-1 RT human hemoglobin


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 oftendegenerate

synonymous vs.nonsynonymous mutations


Molecular Genetics

The Human Karyotype

Most human cells are diploidwith 23 pairs of chromosomes.

22 pairs of autosomes

X, Y sex chromosomes

Exceptions: gametes are haploid andhave 23 chromosomes; red bloodcells lack nuclei altogether.


Molecular Genetics

Contents of the Human Genome

3 billion base pairs per haploidcomplement

23,000 protein-coding genes: exons(2%), introns (24%)

transposable elements (51%) canmove around the genome and manycan replicate

satellite DNA (6%) consists ofnon-coding tandem repeats

Rollins et al. (Genome Research, 2006)


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). Humancells contain from ten to several thousand mitochondria per cell.


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 frommutation, 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 theproduction of four gametes.

Mendelian genetics (Mendel, 1866) explains how offspring inherit genomes andtraits from their parents.


Mendelian Genetics

Mendel’s Law of Segregation

A locus is a position in a genome.

A diploid cell carries two copies of eachlocus called alleles.

Homozygotes have two identical alleles(PP, pp); heterozygotes have two differentalleles (Pp).

Each parent transmits just one of thesetwo alleles to each gamete.

It is usually the case that both copies areequally likely to be transmitted to thegametes.


Mendelian Genetics

Mendel’s Law of Independent Assortment

Each pair of homologous chromosomessegregates independently of the others.

Loci on the same chromosome areusually inherited together, but can bereshuffled by recombination.

Both inter- and intra-chromosomalrecombination are a source of geneticvariation.


Mendelian Genetics

Crossing over during meiosis I produces recombinant gametes.


Mendelian Genetics

Recombination Rates

Recombination (usually) occurs only between homologous chromosomes.

Each pair of homologs undergoes at least one crossover during meiosis, butmultiple crossovers can also occur.

The probability that two loci recombine is an increasing function of the physicaldistance (number of base pairs) between them.


Mendelian Genetics

Non-recombining Markers

The mitochondrion is maternally inherited andso its genome does not recombine.

Most of the Y chromosome is non-recombining, except fortwo short terminal regions that recombine with the X(pseudo-autosomal regions).

Recombination occurs along the entire lengthof the X chromosome in females.

Non-recombining loci share the same genealogy, e.g., theentire mtDNA genome has a single genealogical history.


Mendelian Genetics

References

Alberts, B. et al. (2007) Molecular Biology of the Cell. 5’th edition. GarlandScience.

Krebs, J. E., Goldstein, E. S. and Kilpatrick, S. T. (2011) Lewin’s Genes X. Jonesand Bartlett.

Sturtevant, A. H. and Lewis, E. B. (2001) A History of Genetics. Cold SpringHarbor Laboratory.


genetic variation: overview · traits are determined by genes. each gene can have nitely-many di...

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