Notes from the Thompson:

Definitions
 Locus = a segment of DNA occupying a particular position/location on a
chromosome (gene locus - DNA segment inside a gene)
 Allele = alternative forms of a gene
o WT allele - prevailing, common allele
o Variant (mutant) allele - differs from WT, contains a mutation
(cause disease, increase susceptibility to disease, or no effect)
o Allelic polymorphism – within the population, 2 or more alleles are
common at a locus
 Haplotype = a set of alleles at a locus or cluster of loci on a chromosome
 Genotype = a set of alleles that make up a person’s genetic constitution, at all
loci or a single loci
o Compound heterozygote – genotype of 2 different mutant alleles of
the same gene
 Karyotype = the chromosome consitution of an individual, or a (metaphase)
spread for a photomicrograph
 Phenotype = observable expression of a genotype (morphological, clinical,
cellular, biochemical, presence or absence of disease)
o Pleiotropic = a single abnormal gene or gene pair produces multiple
diverse phenotypes (in different organ systems, at different ages)
 Chromosome disorder – excess or deficiency of (multiple) genes on an
entire chromosome or chromosomal segment (ex. Trisomy 21), common and
often embryonic lethal (half of spontaneous first trimester abortions, 7/
1000 liveborn infants)
 Single gene defect – mutation in a single gene, may be present on one
chromosome or both chromosomes of a pair, 1-2/1000 people, 2% will have
one during lifespan
 Multifactorial (complex) inheritance – genetic component because recurs
in families, but uncharacteristic/not understood inheritance pattern, may
result from multiple genes that interact to cause the disease or predispose an
individual, responsible for majority of diseases (60% will have one during
lifespan)
 Mendelian pattern of inheritance (Mendelian disorders) – single-gene
mutation causes the trait, follows Mendel’s predictions of fixed proportions
of the trait in offspring
 Pedigree – a graphical representation of a family tree
o Kindred – the extended family in the pedigree
o Proband (propositus, index case) – the family member with the
disorder who brought the family to the geneticist’s attention
o Sibship – a family of siblings
o First degree relatives – the parents, children, or siblings; second
degree relatives – the grandparetns, grandchildren, aunts/uncles,
nephews/nieces, half-sibs; third degree relatives – first cousins, etc.
 o Isolated case – only one affected person in a family
o Sporadic case – the proband developed a new mutation
 Penetrance = the probability/frequency that a disease genotype will have
phenotypic expression
 Expressivity = severity of expression of the phenotype among individuals
with the same disease genotype
 Genetic heterogeneity = can mean one or either:
o Allelic heterogeneity = different mutations at the same locus cause
the same disease phenotype
o Locus heterogeneity = mutations at different loci cause the same
disease phenotype
 Incomplete dominance = one allele causes the disease, but homozygotes for
the allele have more severe phenotype
 Imprinting = alterations in the chromatin that occur in the germline of one
parent but not the other at characteristic locations in the genome, causes
differences in gene expression between the allele inherited from the mother
and the allele inherited from the father, reversible, a type of epigenetics
o Ex. C methylation, modification or substitutions in chromatin of
specific histone types
o Imprinting centers – DNA elements inside imprinted regions, that
control conversion of maternally-imprinted DNA in offspring to
different imprint pattern (maternal or paternal)
 Triplet Repeat Expansions (p. 387-8)
o Birth order effect- born last, has the largest number of triplet repeats,
show the most severe symptoms/earliest onset
o Anticipation - triplet repeat expansion, mechanism thought to be
slipped mispairing
 More detail - polymerase slippage during replication: slippage
on Okazaki fragments on the lagging strand. Once the triplet
size reaches a critical threshold, slippage events can occur on
all, or nearly all, Okazaki fragments. This leads to greater and
greater expansion over subsequent generations.
 Happens in proliferating germline cells (spermatogonia) and
somatic cells and nonproliferating germline and somatic cells
 expansion mosaicism (smear on blot)
 Disease mechanism: Repeat section forms stable hairpin loop,
which associates with a number of proteins  this sequesters
these proteins and prevents them from doing their job
 Linkage analysis – method of mapping genes that uses family studies to
determine whether 2 loci (genes) show linkage when passed from one
generation to the next. For complex traits and diseases: if a region of the
genome is shared more frequent than expected by relatives with the disease
phenotype (concordant relatives), infer that shared alleles predispose to the
phenotype at one or more loci in that region
 o Linkage equilibrium – freq of each allele within the haplotype is the
same as freq of that allele in the population as a whole, occurs when
alleles are 1cM or more apart, when not associated with the disease
o Linkage disequilibrium (LD) – haplotypes (alleles) that are not in
linkage equilibrium, 2 alleles always appearing together are in LD, ex.
chromosoes with disease allele D are enriched for allele A (higher
freq) compared with chromosomes that do not carry the disease
allele, model-based (known mode of inheritance: auto dom, auto rec,
x-linked) or model-free
o LD blocks – clusters of neighboring SNPs in high LD within
subpopulations based on ethnicity
 Association study – look for increased frequency of particular alleles (HLA
haplotype or SNP haplotype) in affected compared with unaffected
individuals, pitfall: association  causation, allele may be associated with
disease for other reasons:
o population stratification – isolated subpopulations by ethnicity,
religion that may have increased risk for a particular disease
o alleles in LD will show positive association regardless of function

Pedigree Patterns of single-gene inheritance

 Autosomal recessive
o Affects males and females equally
o Affected child must have gotten one disease allele from each parent
(each parent must have at least one disease allele)
o Skip generation(s)
o Usually 2 unaffected carrier parents (likely consanguineous if
mutation is rare): each child has ¼ chance of having disease/being
recessive homozygote
o Most people are compound heterozygous because any one mutation is
very rare (unless consanguineous marriage, founder effect in an
ethnic group, or no allelic heterogeneity)
 Autosomal dominant
o Affects males and females equally
o Affected child must have affected parent
o Disease appears in every generation (unless new mutation or low
penetrance)
o Usually one affected, one WT parent: each child has ½ chance of
having disease/the mutant allele
o Accounts for majority of mendelian disorders, significant # of new
mutations when very severe disease
 X-linked recessive
o Mostly affect males (females are carriers, but some may have less
severe disease due to x inactivation)
 o Skips 1 generation (or more if multiple female carrier generations):
o Affected male  carrier daughter  affected grandson (½ chance)
o Significant # of new mutations
 X-linked dominant
o Affected females twice as common as males, but usually milder
phenotype
o Pedigree pattern similar to autosomal dominant, but:
 Affected fathers can only have normal sons and affected
daughters (while each child of affected mom has ½ chance of
having disease/mutant X)