Gene Flow, Nonrandom Mating, the Human Genome Project

Gene Flow Example: Lupines

  • Lupines create sub-populations when seeds are swept by wind.
  • A seed from a heterozygous individual founds a new population.
  • Original population: 90% A1, 10% A2.
  • New population (from heterozygote): 50% A1, 50% A2.
  • Pollen transfer between populations is another form of gene flow.

Nonrandom Mating (Assortative Mating)

  • Likes breed with likes, favoring homozygotes and reducing heterozygosity, restricting the gene pool.
  • Self-fertilization exemplifies assortative mating.
  • Consanguineous relationships are an example.
  • Behavioral or seasonal mating strategies can also cause non-random mating.
  • Disassortative mating (unlike mates) increases heterozygosity.

Inbreeding Effect

  • Self-fertilization reduces heterozygotes by 50% per generation.
  • Conservation biology: loss of heterozygosity reduces adaptability.
  • Homozygous individuals are more susceptible to diseases.
  • Consanguineous relationships increase the probability of autosomal recessive disorders.
  • The chance for this female to inherit two copies of her great grandmother's small a allele is 4∗(1/64)=1/164 * (1/64) = 1/16 instead of 1/2∗1/2∗1/2∗1/2∗1/2∗1/2=1/641/2 * 1/2 * 1/2 * 1/2 * 1/2 * 1/2 = 1/64

Inbreeding Depression

  • Assortative mating leads to reduced fitness (survival ability).
  • Children of first-cousin marriages have higher mortality rates.
  • mortality<em>cousin>mortality</em>non−relativemortality<em>{cousin} > mortality</em>{non-relative}
  • Natural selection removes disadvantageous recessive alleles.

Natural Selection

  • Driven by differences in reproductive success based on phenotypes.
  • Positive selection: a phenotype is favored.
  • Negative selection: a phenotype is disfavored in a certain environment.

Types of Natural Selection

  • Stabilizing Selection: Intermediate phenotypes are favored.
    • Reduces genetic variability, but does not change average.
    • Example: human birth weight (6-8 lbs).
  • Disruptive Selection: Extreme phenotypes are favored, intermediates selected against.
    • Maintains genetic variation; can lead to speciation.
    • Example: Darwin's finches, juvenile black-bellied seed crackers.
  • Directional Selection: One extreme phenotype is favored.
    • Example: dog breeding.
    • Before selection, it’s pushed towards the median phenotype.

Directional Selection Example: Anoles

  • Lizards with longer limbs/toes survived a hurricane better.
  • Longer limbs helped them hold on during hurricane.
  • The surviving lizards with longer limbs now repopulate the area.

Reverse Selection

  • Directional selection isn't always irreversible; genetic variation is maintained.
  • Example: Peppered moths adapt the color based on tree color.
    • Industrial melanism: dark moths favored when trees are covered in soot.
    • Clean air laws reversed selection, favoring light-colored moths.

Random Genetic Drift

  • Allele frequencies change due to chance events.
  • May not produce more fit individuals.
  • Pronounced in small populations.

Fixation of an Allele

  • One allele eventually represents the entire population.
  • Can lead to vulnerability if environmental pressures change.
  • Conservation biologists work to increase genetic diversity using biobanks and ART.

Population Bottleneck

  • Sudden decrease in population size (disease, catastrophe).
  • Reduces alleles in the population.
  • Surviving individuals breed, leading to a different frequency in the next generation.
  • Prone to genetic drift.

Founder Effect

  • A group leaves a population to establish a new one.
  • New population's allele frequency differs from the original.
  • Isolated habitats (islands, mountains, caves) increase this effect.
  • Reduces genetic diversity and increases inbreeding.

The Human Genome Project (HGP)

  • Started due to radiation-induced mutations from atomic bombs and their effect on the human genome.
  • Aimed to identify replication, DNA damage, and repair.
  • Officially began in 1990.
  • International effort aiming to map/sequence 30-35,000 human genes with resolution 2–5 centimorgans.
  • Goals for HGP:
    • A high-resolution genetic map.
    • Physical map of human chromosomes and selected model organisms.
    • Identify landmarks on DNA.
    • Completely sequence what they select.
  • Model organisms:
    • E. coli
    • Yeast
    • C. elegans
    • Fruit flies
    • Arabidopsis thaliana

Success of HGP

  • Met goals sooner and cheaper than expected.
  • September 1994: The high resolution genetic map with 1 cm resolution and 3000 markers.
  • April 2003: Exceeded sequencing goal and cheaper execution.
  • Two teams:
    • Funded by the government.
    • Celera Genomics (Craig Venter).
  • Hierarchical sequencing vs. Shotgun sequencing:
    • The hierarchical strategy is cutting up many copies of the genome into pretty large fragments into artifical chromosomes.
    • The shotgun strategy clones them into precise fragment lengths and then sequences them.

Completion

  • First draft sequence: February 2001.
  • Public consortium published in Nature, Celera Genomics in Science.
  • The final sequence was 99.9% with ~ 341 defined gaps.
  • Other species: chimpanzee, rhesus monkey, mouse, rat, marsupial, cat, dog, cows etc sequenced.
  • Platypus Sequencing:
    • The platypus is closer to birds and reptiles than other mammals.
  • All data deposited into public databases and is made freely available.

Interesting Features

  • 3.16 billion base pairs of DNA, about 20-25,000 genes.
  • Average gene size: around 3,000 base pairs.
  • Dystrophin gene, is a huge gene with 2,400,000 base pairs.
  • 2% of the genome: coding regions vs the 98% with no known functions.
  • Chromosome with the most genes: chromosome 1: ~ 2,968.
  • Chromosome with the least genes is the Y chromosome: 231.
  • 99.9% of human DNA is the same. But we all look so different.

Potential Applications

  • Molecular medicine
  • Microbial genetics
  • Risk assessment
  • Forensics
  • Livestock breeding
  • Anthropology research

The Goal of HGP

  • The goal of the Human Genome Project was to use this information to develop new ways to diagnose and thus treat or cure or prevent diseases.
  • Diagnostic tests: Ethical considerations - test results can jeopardize a person's employment/insurance status.

Mutations

  • Currently, we've identified 1400 human disease-causing genes and most human genetic diseases are still yet unknown.
  • Single base mutation / SNPs can lead to disease.
  • Types of mutations with an example in a sequence.
    • Silent mutation: A mutation that does not affect the amino acid sequence.
    • Conservative missense mutation: t in our normal sequence has now been mutated to an a, this is creating something called threonine a closely related amino acid.
    • Nonconservative missense mutation is when we see something significantly different occur, for example serine, now it's proline which will change the way the protein sequence folds.
    • Nonsense mutation changing the c from up here into an a actually turns this into a stop codon.
    • Frameshift mutation everything on the other side of this has been altered, so it's been shifted and it does affect the genes downstream.
  • Genetic diseases mapped to individual chromosomes.