WEEK 3 (STUDY GROUP) Flashcards
Locus
position of an allele on a chromosome
Allele
variant DNA sites at a particular locus
Hemizygous
only one allele because only one chromosome (e.g. X in males, deletions)
Mendel’s three laws
- Segregation
- Independent Assortment
- Dominance
Law of segregation
Equal probability that an allele will be transmitted to offspring
Law of independent assortment
Transmission of alleles at different loci is independent (linked genes an exception)
Law of dominance
A dominant allele completely masks the effect of a recessive allele
First degree relative
parents, siblings, children
Second degree relative
shares a quarter of genes (grandparents, aunts/uncles, nephews/nieces, grandchildren)
Third degree relative
cousins, great-grandparents, great-grandchildren
Genotype
alleles present at one or more loci
Phenotype
clinical, biochemical, physiological, or morphological characteristics of an individual
Phenocopy
presence of a particular phenotype, NOT due to the same inherited genotype
Penetrance
proportion of individuals with a genotype that exhibit disease phenotype
Variable expressivity
individuals with disease-associated allele are all affected, although with variable clinical presentation (e.g. age of onset, severity)
Autosomes
Non-sex chromosomes, 44 (22 from mother, 22 from father)
Autosomal dominant inheritance
a dominant allele completely masks the effect of a recessive allele
Autosomal dominant pedigrees x3
- every generation has affected individuals
- unaffected family do not transmit phenotype to their children
- males and femals BOTH affected and BOTH sexes transmit disorder
(with exceptions)
Exceptions to autosomal dominant rules x2
- De novo variants
2. incomplete penetrance (skip generations)
Recurrence risk x3
- likelihood of two individuals having an affected child.
- Independent for each pregnancy
- Differs by sex for x-linked disorders
Genetic fitness
probability of an individual transmitting their genetic material to the next generation compared to the average probability of the population (e.g. lethality in early age = 0 vs. no effect on reproduction until old age = 1)
Autosomal recessive inheritance
disease only manifests when disease-associated alleles are present on BOTH chromosomes
Autosomal recessive pedigrees x4
- typically occurs in single generation
- parents are asymptomatic carriers
- males and females both affected
- alleles tend to be rare in populations*
Compound heterozygosity
two different disease-associated alleles in the same gene maternally AND paternally inherited (e.g. both parents heterozygote)
Consanguinity consequences x2
increased likelihood to
1. have rare variants that are recessive
- to inherit same disease-associated allele from both parents
Founder effects
increase likelihood to inherit same disease-associated allele from both parents due to reproductive isolation of population (e.g. islands)
Selective advantage
variant that causes a recessive disease in homozygous state can be maintained in population at high levels if heterozygous state offers some benefit (e.g. sickle cell, CF)
Nettie Stevens
discovered sex chromosomes. NOT Thomas Hunt Morgan
X vs. Y gene content
~900 vs. 55 genes (important for male sex determination/characteristics)
X-inactivation
dosage compensation due to increase in gene-rich X. Clonal process (i.e. every daughter cell will have same X inactivated)
X-linked dominant pedigrees x3
- Looks similar to autosomal dominant, every generation has affected individuals BUT
- affected males DON’T have affected sons
- ALL daughters of affected mails are affected
Male lethality pedigree
due to lack of X-inactivation in males. Only affected females, multiple miscarriages.
X-linked recessive pedigrees x4
- generally, females not affected
- allele is never transmitted directly from father to son, but allele transmitted to all daughters
- allele transmitted through multiple carrier females
- isolated cases often due to de novo variants
Exception to Mendel’s 2nd law (Independent Assortment)
Linked genes. Due to recombination in meiosis, genetic material closer together is more likely to be inherited together.
Massively parallel DNA sequencing (NGS)
probes designed complementary to exonic coding regions, aligned using reference genome.
Gene panel
probes designed to specific genes known to be implicated in a particular disease
Exome seuqencing
All known genes in genome are sequenced, broadly applicable to all genetic disorders
Full genome sequencing
ALL regions, including introns. For SNVs (single nucleotide variants), indels, structural variants, STRs (short tandem repeats)
Heritability
proportion of variability in a trait caused by genetic factors
Equation for heritability
H^2 = Vg / (Vg + Ve);; Vg is variance due to genetics and Ve is due to environment
Method used to traditionally calculate heritability
Twin studies – phenotypic concordance among identical (MZ) twins is compared to concordance among non-identical (DZ twins). Because they share the ‘same environment’ the difference in phenotype is attributed to genetics
What is additivity
Additivity is where many variants each individually contribute to overall trait variation
Threshold model
Threshold model: an individual has disease if the collective effects of each additive allele, along with the environmental component, cross a certain ‘threshold’
Quantitative trait
Quantitative trait: genetics and environment both contribute additively to a continuous measure (e.g. height, LDL, blood pressure, etc.)
How is recurrence risk calculated
By comparing distribution of a quantitative trait among general population to affected family members, we can estimate where this threshold is and calculate recurrence risk
How does Genome Wide Assoc. Study work and its goal?
Compares cases (eg. people who have heart disease) to control (eg. people who don’t have heart disease) and compare their allele frequency to see if they are associated with certain diseases.
What is polygenic risk score
estimate of disease risk calculated from genotypes at many different GWAS-derived risk loci
Duchene muscular dystrophy – what type of disease? What gene?
X linked recessive disorder; genotype phenotype correlation. Variant in DMD which codes for dystrophin (needed in muscles). Out of frame variant = severe disease. In frame (eg. missense) = mild disease (Becker muscular dystrophy). Females at increased risk of dilated cardiomyopathy – an eg of how females can be lowkey affected even as a carrier in a recessive x linked disease.
X linked dominant
X-linked dominant disorders are caused by mutations in genes on the X chromosome, one of the two sex chromosomes in each cell. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).
X linked recessive
X-linked recessive disorders are also caused by mutations in genes on the X chromosome. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission). Affected males –> Affected daughters.
Alport syndrome – what type of disease? What gene?
X linked dominant. Variant in COL4A5 which affects collagen fibers. Genotype phenotype correlation – truncating (frameshift, deletion, premature stop) is more severe than missense, dominant negative.
Oral facial digital syndrome type I
X linked dominant. Variant in OFD 1. Male lethality during development, so only females affected mostly. (except disproved– case study on some males were born w it because of in frame variant)
PCDH assoc. epilepsy
Female restricted disorder, males are carriers. Those without mutation can create protocadherin and communicate; males with carrier don’t make the protein but can still communicate; female carriers have a mix of normal protocadherin and mutated version, so cells can’t communicate.
Example of x inactivation escape artists?
Cdls (cornelia de lange) and SMCI A assoc epilepsy
46, XY disorder of sex development
Y linked disorder, SRY gene depleted so patients have XY chromosome but are female presenting
Why are clinical features typically more severe in males than females who carry a pathogenic variant in a gene
associated with X-linked dominant inheritance?
Males have only one X chromosome while females have two. In general, random X chromosome inactivation
predicts that 50% of the female’s cell’s will express the unaltered allele and generate functional protein.
What is gene dosage?
Refers to the number of copies of a particular gene, of particular importance for the X chromosome as females
have two copies of the X chromosome to males 1.
- Why is the usefulness of the terms ‘dominant’ and ‘recessive’ debatable for X-linked disorders?
A significant proportion (if not majority) of females that carry X-linked pathogenic variants have some features of
the disorder, though they are normally much milder, or may only present a subset of the features.
- What is skewed X-inactivation?
Skewed X-inactivation can occur when the one X-chromosome is preferentially inactivated, This can happen if
there is a cell survival or proliferative disadvantage for those cells expressing the X chromosome with the altered
allele. Thus, it is a common for female carrier to show skewed X-inactivation (the pathogenic variant is
preferentially inactivated) for certain disorders including immunodeficiencies and intellectual disabilities.
- Why are there so many more genes associated with disease that occur on the X chromosome and compared to the
Y?
The X chromosome has ~900 genes to the Y chromosomes ~55.
