Unit 2 Flashcards
Penetrance
-The fraction of individuals with a trait (disease) genotype who show manifestations of the disease. If all persons carrying a mutation have the trait, the condition is 100% penetrant. If some mutation carriers do not show signs of the trait, penetrance is incomplete (
Expressivity
The degree to which a trait is expressed in an individual (is a measure of severity). Expressivity is analogous to a light dimmer (the light is ‘on’ but the brightness (expressivity) exists along a spectrum (of severity)). The variation in phenotype is explained (in part) by sex influence, environmental factors, stochastic effects, and modifier genes
Sex influence and sex limitation
Phenotypic expression in some conditions is dependent on the individual’s sex (e.g. gout is more common in males than premenopausal females). Sex limitation occurs if only one sex can express a phenotype (e.g. unicornuate uterus).
Stochastic Effects on Mendelian gene patterns
Stochastic (random) effects can influence the expression of
phenotypes. This concept pays homage to the fact that some phenotypes may be influenced by chance events/processes absent any obvious genetic/environmental factor.
Modifier genes and Mendelian inheritance
Genetic factors outside of the genetic locus causing a disease can be important for the expression of Mendelian diseases.
Phenocopies
Diseases (traits) that are due to non-genetic factors. Example: A thyroid cancer due to radiation exposure cannot always be distinguished from a thyroid cancer due to mutations in RET gene.
Pleiotropy
Used to describe multiple different phenotypic effects due to mutation(s) in a single gene. Often used, when the phenotypes are seemingly unrelated and/or in multiple different tissues. Example: Neurofibromatosis Type I leads to: café au lait spots (skin), neurofibromas (peripheral nervous tissue), hammartomas in the eyes (ocular), abnormal freckling (skin again), and learning difficulties (central nervous system).
Polymorphism:
A genetic variant (mutation) which is common (>1%) in the populations
Founder effects:
a high frequency of a mutant allele in a population founded by a small ancestral
group when one or more of the original founders was a carrier of the mutant allele
Genetic drift:
random fluctuation of allele frequencies, usually in small populations
Estimating Autosomal dominant mutation rates (direct method)
For autosomal dominant conditions with 100% penetrance one can simply count
the number of new cases that occur with no family history. For example, if 12 disease cases are
identified in 100,000 children and 10 of the 12 cases have a negative family history, then the
mutation rate is 10/100,000 children. Since each child actually as 2 alleles for each gene the
theoretical gene ‘mutation-rate’ (μ) is 10/200,000, or 1/20,000 alleles
Estimating autosomal dominant mutation rates (indirect method)
For an autosomal dominant condition where the reproductive fitness (f) is zero
(i.e. affected persons do not survive to reproduce and/or are infertile) then all cases represent new
mutations. Since each child inherits 2 genes (each could mutate) then the incidence (I) of disease
is really twice the mutation rate I = 2μ.
Mutation rate estimation for nonzero fitness
Autosomal dominant: μ= 1/2 F (1-f) Autosomal recessive μ= F (1-f) X-linked recessive μ= 1/3 F (1-f) mu= mutation rate f=fitness F=frequency of disease
Hardy-Weinberg equation
p^2+ 2pq + q^2= 1.
In rare conditions q is small, making q^2
very small so 2pq»_space; q^2. This means that
most copies of the minor allele are found in
heterozygotes.
Idealized Assumptions in Hardy-Weinberg Equilibrium (HWE):
Large population mating randomly
Allele frequencies remain constant over time because:
o No appreciable rate of new mutation
o No selection for/against any allele
o No appreciable immigration/emigration of persons from population with different allele
frequencies
Stratification (Non-random mating)
refers to populations containing 2 or more subgroups which tend preferentially mate
within their own subgroup. Mate selection is not dependent on the trait/disease or interest.
(Example: sickle cell anemia in African Americans (AAs) has hig
Assortive mating
refers to when the choice of mate is dependent (in part) on a particular trait (or
sometimes a disease). This occurs because people tend to choose mates who resemble
themselves for (language, intelligence, height, skin color, etc.). This has been observed for
congenital short stature (previously called ‘dwarfism’), blindness, and deafness.
Consanguinity,
occurs when persons marry closely-related blood relatives. This, non-random,
mating practice increases matings between carriers of autosomal recessive diseases, thereby
increasing the number of cases of autosomal recessive diseases in the population.2
Mendel’s law of segregation
Law of Segregation:
At meiosis each allele (2) of a single gene separates/segregates into different gametes –> 50/50 ratio
Basically, all the alleles split up into different gametes
Mendel’s law of independent assortment
Law of Independent Assortment:
At meiosis the segregation of each pair of alleles in >= 2 genes is independent –> each 50/50 ratio
Separate genes for separate traits are passed along to offspring independently of one another – they’re ‘independently assorted’
X-linked recessive inheritance pattern
X-linked recessive:
- if you’re female, will not display phenotype, but will be a carrier
- if you’re male, and your mother is a carrier, you have a chance of getting it. If your father is a carrier, you will not get it
X-linked dominant inheritance
- if the father has it – all daughters will definitely display phenotype. Sons will not.
- if the mother has it – daughters & sons may get it
Three “threats” to mendelian inheritance
Penetrance:
Affected/unaffected
(lightswitch)
Expressivity:
Severity
(Dimmer)
Pleiotropy:
Localized or multi-system?
(Lights on in several rooms of house, or just one?
Size of human genome
- 3 x 10^9 bp
Prevalence of new mutations in an individual
~30 new mutations occur in every individual
Prevalence of a SNP between two individuals
Average of 1 SNP every 1000 bp between any two randomly chosen human genomes.
**Detectable by PCR–> easy to score, widely distributable
Indels: Minisatellites
tandemly repeated 10-100 bp blocks of DNA
VNTR (variable number of tandem repeats)
Indels: Microsatellites
-di-, tri-, tetra-nucleotide repeats
->5 x 104 per genome
STRPs (Short Tandem Repeat Polymorphisms)
CNV’s
- variation in segments of genome from 200 bp – 2 Mb
- can range from one additional copy to many
- array comparative genomic hybridization (array CGH)
Gene Poor chromosomes
Chr 13, 18, 21 (aneuploidy)
Unstable regions of the genome
1q21; chr 5q13 (SMA);chr 22q (Digeorge)
GC/AT rich portions of genome
38%/54%, respectively. Clustering allows bands to appear on karyotypes
Status of sequencing of the euchromatic genome
99% of the euchromatic genome is sequenced & is accurate to an error rate of 1 event per 100,000 bp
Many (>200) sequence gaps remain in eurochromatic DNA
Many of the remaining gaps are associated with segmental duplications
Frequency of categories of genomic DNA sequences
1) 1.5% is translated (protein coding)
2) 20-25% is represented by genes (exons, introns, flanking sequences involved in regulating gene expression)
3) 50% “single copy” sequences
4) 40-50% classes of “repetitive DNA”
Sequences that are repeated hundreds to millions of times
Human specific pentanucleotide tandem repeat
found in heterochromatic regions on chr 1, 9, 16, Y: Hotspots for human-specific evolutionary change
Dispersed repetitive elements
Alu (short, ~300 bps, ~500k copies)
L1 (long, ~6 kb, ~100k copies)
-Often retrotransposed (insertional inactivation possible)
-Repeats may facilitate aberrant recombination leading to disease
Number of human genes
25k-30k; includes protein coding genes, RNA encoding genes, and pseudogenes
Gene Families
. A gene family is composed of genes with high sequence similarity (e.g. >85-90%) that may carry out similar but distinct functions. Some are clustered, some are dispersed. Gene families arise through gene duplication, a major mechanism underlying evolutionary change.
(when a gene duplicates it frees up one copy to vary while the other copy continues to carry out a critical function)
CNV’s
- Possible prevalent because gene duplication has evolutionary advantage
- CNV loci may cover 12% of genome
- CNVV regions are often enriched for human specific gene duplications, genome sequence gaps, and human disease
CNV regions associated with disease
1q21.1(everything, see other card); 9p13.3-9q21.1(Alfi’s syndrome); 5q13.3 (SMA)
DUF1220/NBPF sequences
deletions or repeats of these sequences in the 1q21 region are associated with disease.
Deletions–>microcephaly, SZD
Duplications–>Macrocephaly, ASD
Limitations of Nextgen sequencing
Complex, highly duplicated regions are typically unexamined
Such regions are implicated in numerous diseases, e.g. 1q21
Relies on short read sequences, no mammalian genome has been completely sequenced
Limitations of GWAS
–“Missing heritability” for complex diseases: Many large-scale studies implicate loci (e.g. SNPs) that account for only a small fraction of the expected genetic contribution
– Many regions of the genomes are unexamined by available “genome-wide” screening technologies: is this where the “missing heritability” lies?
Triploidy
Three of every chromosome (69XXX, 69 XXY, 69 XYY)
Formed when one 2n gamete joins a 1n gamete
Trisomy
Three copies of one chromosome. (47 XX +21)
Monosomy
45, X (Turner Syndrome)
Mosaicism
47, XXX/46,XX
Trisomy 18
Edwards Syndrome–> intrauterine growth retardation, characteristic faces, severe intellectual disabilities, characteristic hand positioning, congenital malformations (valvular heart disease, posterior fossa CNA maldevelopment, diaphragmatic hernia, renal abnormalities)
Perinatal fatality~90%
Trisomy 13
Patau Syndrome - Characteristic faces, severe intellectual disability, congenital malformations (holoprosencephaly, facial clefts, polydactyly, renal abnormalities_
Polyploidy
Having a multiple of all of the chromosomes greater than 23 (Triploid=69, tetraploid= 92–occurs when DNA replication occurs without cell division)
Aneuploidy
Incomplete set (Trisomy or monosomy)
Tissue samples for Constitutional cytogenetic studies
Prenatal: Amniotic fluid or chorionic villus
Postnatal: peripheral blood or skin biopsy
Tissue samples for cancer cytogenetic studies
bone marrow, solid tumor, peripheral blood, lymph node, CNS
Genetic cause of Trisomy 21
Majority result of maternal meiosis I nondisjunction errors; ~4% are associated with a parental balanced translocation
45,X
Turner Syndrome
- Prenatal lymphedema/cystic hygroma
- Congenital malformations – heart disease (coarctation of aorta), gonadal dysgenesis, short stature, webbed neck
- 25% have mosaicism, thought to contribute to survival
- Most severe phenotypes– tiny ring or tiny marker chromosome
Cytogenetics of structural abnormalities
Structural abnormality must be >5000 kb to be visible on a karyotype
Balanced Translocations
No loss or gain of genetic material
No phenotypic effect for heterozygote carrier
Exception: breakpoint in a gene, disrupting function
Robertsonian Translocation
fusion of two acrocentric chromosomes within their centromeric regions, resulting in the loss of both short arms (these short arms contain rDNA repeats, so the loss of these is not deleterious)
a. Phenotypically normal, but their offspring may have phenotypic mutations
75% are 13/15 RT’s
Reciprocal Translocation (Alternate segregation)
From quadrivalent state:
(A) got very lucky; both unbroken chromosomes got transferred to gamete
or
(B)chromosomes get transferred that end up containing complete genetic information
Reciprocal translocation (Adjacent 1)
From quadrivalent state:
- Abnormal segregation
- Adjacent, or next door, non-homologous centromeres go to same pole
- Most common form of mal-segregation when translocated segments are relatively small
- results in trisomy and monosomy for some segments
