Human Genetics Flashcards
what are some advantages vs disadvantages to studying human genetics?
advantages:
-model system for humans
-anyone with a serious medical condition will end up at the doctor’s, which is a phenotypic detection machine
-a lot of money going into genetics research
disadvantages:
-long generation time like 25 years
-can’t choose your progeny and you have very few progeny per cross
-can’t do transgenesis
indels
insertions or deletions
polymorphism
has to be in at least 1% in the species that you’re studying
haplotype
look at a region in a chromosome in a person from today and see a similar region in an ancestor –> region on chromosome that gets passed through together
linkage equilibrium
set of ancestral alleles that are allowed to undergo meiotic recombination for many generations without any mutations
linkage disequilibrium
-very common in humans since we are a relatively young species and have not had many generations to perform recombination
what do different degrees of diversity reflect?
- population bottlenecks- drastic reduction in the size of a population leading to a decrease in genetic diversity within that population as only a small subset of the population can survive
- the time during which mutations have been accumulating
mitochondrial DNA
-passed through mom since the egg has all of the mitochondrial DNA that gets passed on
-heteroplasmy- different levels of mitochondrial DNA in each cells so only when the level reaches a certain threshold will there be phenotype penetrance
monogenic vs multigenic disease
-monogenic- one gene –> mutation in the gene, you get a phenotype
-multigenic- it could mean that to have the phenotype you need mutations in each of several genes, each of more than one gene, or it could mean that the sam phenotype can arise from individuals in each of multiple genes (series of monogenic disorders)
exome sequencing
-sequence all of the protein-coding genes
-fragment the genome –> put adaptors on the ends and PCR amplify –> take the amplified fragments and select them with synthetic DNA fragments, which each have little biotin parts to them to capture all of the chromosomal fragments that were hybridized to the synthetic DNA
exome sequencing strategy: autosomal recessive disease
-you can ask which sequence variants are shared between the two affecteds but are not present int he unaffected sibling
-if it’s a consanguineous union, you could ask not only what’s shared but what’s shared in homozygous fashion
copy number variation
-big chunk of DNA that might encompass a lot of genes
-you could have one copy of it, extra copy, or no copies
-look to see which regions are the biggest that get duplicated
GWAS
-type for markers along the genome and ask in a population that has a trait vs an ethnically matched control that doesn’t, is the ratio of alleles the same in each place in the genome?
-since you’re interrogating a million places in the genome, the chance that these two populations might differ from each other, just as a random event, is not that rare for any given polymorphic marker –> bonerferroni correction so you lower the threshold that p value has to be below for it to be statistically significant
twin studies
-pairs of people who have identical genomes are very similar
-take pairs of twins, either identical or fraternal, and within each pair you ask for some variable
-see if monozygotics have a higher correlation vs dizygotics
-if there is a higher mz value and lower dz value then there is a higher heritability score
falconer’s formula
H^2 = 2(rmz-rdz)
heritability can be determined by monozygotic or dizygotic twins
-what part of the variance of a trait is explained by genetics
hardy-weinberg equilibrium
-for people: p^2 + 2pq + q^2 = 1
-for alleles: p + q = 1
what does HWE assume?
-random mating
-no mutations
-no migration or gene flow
-no selection
-infinitely large population
inbreeding
-people marry and have kids with individuals who are genetically related
single nucleotide polymorphisms (SNPs)
variant or minor allele that is present in the population @ a frequency of at least 1%
single nucleotide variant
site that differs from reference genome
types of SNPs
- frameshift- changes the way a sequence is read during translation –> any insertion or deletion that is not a multiple of 3
- silent- nucleotide is substituted for one that still permits the proper amino acid to be incorporated
- missense- nucleotide is substituted for one that encodes a different amino acid –> certain ones can be more deleterious than others
- nonsense- mutation changes an amino acid into a stop codon
indels
-insertions, deletions, or multi-base substitutions (<50 bp)
-<1% of DNA changes are numerical or structural changes
aneuploidy
numerical changes
structural
inversions, deletions, insertions, duplications, translocations of chromosomes
what are examples of mendelian disorders?
sickle cell anemia (autosomal recessive), cystic fibrosis (autosomal recessive), and duchenne’s muscular dystrophy (x-linked recessive)
what are mendel’s 3 laws of inheritance?
- law of dominance- when 2 alleles of an inherited pair are heterozygous, allele that is expressed is dominant and allele not expressed is recessive
- law of segregation- a diploid organism passes a randomly selected copy of each allele to one of its gametes
- law of independent assortment- when each of these alleles are sorted into gametes, they’re done so independently
-inheritance of an allele of one gene has no impact on the likelihood of inheriting a particular allele of a different gene
how to evaluate pedigrees
- transmission- are affected family members in every generation (vertical pattern) or does it skip?
- sex differences- what is the ratio of affected males to females?
- segregation- is disease/gene being passed through unaffected carriers? is there male-to-male transmission? is there female-only transmission? what % of children are affected?
autosomal dominant
disease in every generation, transmission to and from both sexes, no transmission from unaffected individuals, affected individuals have a 50% risk of transmitting to offspring
autosomal recessive
-horizontal pattern of inheritance where multiple members of a generation may be affected but trait skips generation
-parents are often unaffected (carriers are unmarked) and the risk of transmitting to offspring ~25%
-consanguinity increases the likelihood that 2 individuals share a rare allele
x-linked recessive
-only males are typically affected –> males are hemizygous for disease allele on the X chromosome
-certain traits may infrequently manifest homozygous females
-hemophilia, muscular dystrophy, and other traits may be embryonic lethal
-females are carriers
x-linked dominant
-inheritance of a single disease allele on X chromosome is sufficient to cause disease
-affected females have 50% risk of transmission
-affected females have ~100% risk of transmission
-affected males have 100% risk of transmission to daughter
paternal imprinting
-imprinting that arises from genetic modifications
-paternal allele is inherited in silent state and affected fathers give rise to carrier offspring @ 50%, while affected mothers give rise to affected offspring @ 50% as well as if they are carriers
maternal imprinting
maternal allele is inherited in silent state
mitochondrial
maternal transmission only
multifactoral
-refers to continuous phenotype
-includes both environmental and genetic factors Ex. diabetes, Alzheimer’s, and cardiovascular disease
incomplete penetrance
not all individuals with an associated genotype express the associated phenotype
de novo
a “new” mutation arises due to mutagenesis in parental gametes
heritability
proportion of the variance of a trait due to genetic factors alone
recombination and gene mapping
-close together 2 chromosomal regions are, the less likely they are to separate during recombination
-1 cM = 1 Mb = 1% RF
linkage disequilibrium
-certain alleles, if close enough together on chromosome will be inherited together @ increased frequency relative to alleles that are on different chromosomes or far apart on the same chromosome
-genes are in LD if they recombine at frequency <50% –> genes are considered linked
-selection, gene flow, and genetic drift maintain LD
haplotypes
combo of alleles on same chromosome that tend to be inherited together
linkage studies
-build on following recent recombo events in families and tests for co-segregation between a genetic marker and phenotype of interest –> most powerful when searching for loci responsible for highly penetrant mendelian
-tend to characterize Mendelian disorders
gwas
-most powerful when searching for relatively common variation in the general population
-tend to characterize common multifactorial diseases
pitfalls of GWAS
- population stratification- can arise due to sampling bias and you get false positive associations due to multiple testing –> decrease the p value significance threshold
- biologically agnostic- cannot provide info on which cell types or tissues are relevant to disease
- relies on LD- cannot distinguish the pathogenic variant from all other variants within LD
what makes you diverge from HWE?
-inbreeding or non-random mating
-gene flow or migration between subpopulations
-genetic drift which can arise through founder’s effect
-mutations and selective pressures
chi squared test
-observed genotype frequency and expected genotype frequency
-if there is a large difference between the two, the population is unlikely to be in HWE
ID by state
identical alleles in two or more individuals
ID by descent
alleles shared between individuals resulting from shared inheritance of those alleles from a common ancestor
inbreeding coefficient
if a child is produced from consanguinious mating, the inbreeding coefficient is the kinship coefficient of the parents
importance of understanding human genetic variation
-making drugs and you need a variant to inform drug targets and genetic differences can affect individual drug metabolism
-developing targeted gene therapies- spinal muscular atrophy- deletions or point mutations in SMN1
-transplant efficacy- blood type, HLA, antibody production dictate the success of these procedures
-designing effective screening procedures- Rh incompatibility can be managed if detected and treated
