bio 460 exam 2

model organisms

short generation time, so researchers can study several generations quickly, similar to humans relevant to the question, sequenced genome so researchers know its DNA

controlled breeding

help us understand gene function, mice have more similarity in body structure to humans, “knockout” shows what happens when a gene stops functioning

• a gene can retain a similar function across species over evolutionary time (conservation)

primates as model organisms

phylogenetically similar to humans, but ethical concerns, long generation times, high costs, fewer tools for genetic manipulation

chimps as model organisms

closest cousins, many captive chimps bred for research, we can learn by investigating the genomes of our relatives

polymorphism and substitution

poly - genetic variation within a species

sub - fixed difference between species

these genetic differences explain our phenotypic differences

phylogenetic reconstruction

species with more similar genome sequences likely share a more recent common ancestor than species with more sequence differences, humans are more closely related to chimps than chimps and gorillas

why some DNA regions suggest a different relationship

humans and gorillas group together or chimps and gorillas group together because of incomplete lineage sorting - haplotype variation present in common ancestor of all 3 species and persisted until the divergence of human/chimp

outgroup

species outside the main group being compared, helps researchers infer which DNA version was ancestral and which changed, orangutan would be good since it has A base like chimps, humans have C

DNA differences can affect traits

coding change - alters protein itself

regulatory change - alters when where or how much a gene is expressed

• humans and chimp proteins are very similar which shows the idea that changes in gene regulation may explain important differences between us

dN/dS

compares the rate of amino acid changing substitutions with the rate of synonymous substitutions

• < 1 - purifying selection, AA changes removed

• = 1 - neutral evolution, neither has a fixation

• > 1 - positive selection, AA changes favored

nonsynonymous vs synonymous

occur at the same rates but are not fixed at the same rates, there are more opportunities for nonsynonymous changes than synonymous because of how the genetic code works, so divide each count by corresponding number of sites first

SEMG2

encodes a protein involved in semen coagulation, greater sperm competition = larger testes relative to body size, higher sperm production, higher dN/dS

positive selection genes

immune defense, sensory perception, male reproduction, these involve changing challenges like pathogens or reproductive competition

human accelerated regions

difficult to study because we can’t predict what every noncoding DNA change does, find regions that stayed similar across many species or accumulated unusually many changes in the human lineage

experiment

13 human-specific substitutions within an 81 bp stretch, researchers attached regulatory sequences from different species to a reported gene and tested them in mice, human-specific DNA changes altered regulatory activity in the experiment but unsure if those changes actually contributed to human wrist anatomy or toolmaking ability

what makes us a human is difficult to identify

even a small percentage difference represents millions of DNA differences, researcher face problems:

• many differences may have little functional effect

• regulatory effect are difficult to predict

• traits may depend on changes across many genes

• a single substitution can be missed by methods looking for repeated adaptive behaviors

• showing a DNA difference is easier than proving its effect on anatomy or behavior

trait mapping

locating genetic variants that contribute to a trait

genetic - variant or region is inherited along with the trait

functional - experiments show how the variant affects biological function

main idea behind mapping

if a trait is at least partly heritable, then the responsible variant(s) must be in there somewhere, find its location without initially knowing what the gene does or sequencing every variant, track genetic markers through families and if it’s close to disease variant then they are inherited together (genetic linkage)

distances between markers and genes

close together - usually inherited together

farther apart - more opportunities for recombination to separate them

STR

high variability, good for linkage mapping in families, high slippage - adding or removing repeat units, usually 2-6 base pairs long

STRs for family mapping

many possible alleles makes it easier to distinguish chromosome inherited from one relative from the chromosome inherited from another, STRs can distinguish people in forensics

haplotype

set of variants carried together on one chromosome, affected parent can carry the disease within a large haplotype, recombination can break it into smaller pieces in descendants

LOD scores

researchers test markers through the genome and summarize support for linkage using these, higher peak means stronger evidence for linkage in that region, strongest peak is a region to look at

linkage mapping - tooth agenesis example

autosomal dominant, track inheritance, map trait to chr 17, investigate candidate genes within that region, identify potentially damaging variant, gather additional biological evidence, mapped region had 80 genes, researchers looked at AXIN2 and identified a stop codon in affected people and expression in developing mouse dental tissues

OMIM

catalogue of genetic conditions, phenotypes, and associated genes, identifying disease variant can help family/affected people, learn about biology of the disease/phenotype, learn about biology of the gene involved

exome sequencing

exome - collection of exons across the genome, the sequencing focuses on protein-coding regions of genes, gives a way to search many genes at once

• miller syndrome - DHOH encodes enzyme, one person’s symptoms may involve more than one genetic condition

exome vs whole-gene sequencing

exome - coding exons, focus on variants whose protein effects are easier to interpret, can miss variants outside captured regions

whole - coding and noncoding, broader search, many noncoding effects are difficult to interpret

height

genetic and environmental, improved env conditions can increase average height faster than genetic evolution like better nutrition as a childe

environmental factors that affect height

diet in childhood, rate/level of childhood illness, medicinal intake, level of exercise, prenatal environment, adult health

additive genetic and environmental effects

additive - both combine without changing each other’s effects, parallel lines indicate no gene x env interaction on the scale

gene x env interaction

occurs when the effect of an env exposure differs depending on genotype

graph patterns

no variation - flat line, genetic effect - separate flat lines, env effect - same sloping line, additive - separate parallel lines, gene x env - lines w diff slopes, reverse - crossing lines

MAOA

encodes enzyme involved in breaking down neurotransmitters like dopamine and norepinephrine, they process responses to stress, different promoter alleles lead to different expression, located on X chromosome

MAOA and maltreatment

low-MAOA shows larger increase in the outcome as maltreatment increases, high shows smaller increase

asthma and env context

age and timing, env includes tobacco smoke, air pollution, infection, exposure, timing can matter and effects differ between genetic groups

CD14 and endotoxin exposure

involved in innate immune recognition of bacterial LPS, difference in response is evidence for G x E, endotoxin association with the outcome depends on genetic contextc

cofounding variables

cofounder can distort observed relationship because it is associated with the factor being studied and influences the outcome, correlation doesn’t automatically establish causation