Day1Part1-Pedigree,Mendel,Genome Organization

Question 1

Define: proband

Answer 1

AKA propositus or index case. The affected idiidual through whom a family with a genetic disortic is ascertained

Question 2

Define: consultand

Answer 2

The individual (not necessarily affected) who presents for genetic evaluation and through whom a family with an inherited disorder comes to attention

Question 3

Features of autosomal dominant inheritance

Answer 3

AKA “vertical inheritance.” Males and females equally affected. Can see male-to-male transmission. All affected individuals will have at least 1 parent who carries the allele. With each pregnancy; there is a 50% chance to offspring will inherit the disease.

Question 4

Features of autosomal recessive inheritance

Answer 4

Males and females affected equally. Typically the parents are gene carriers. There is a 25% chance the offspring will be affected; a 50% chance the offspring will be a carrier; and a 25% chance will inherit no copies of the disease allele.

Question 5

Features of X-linked dominant inheritance

Answer 5

When a female is affected; offspring has 50% chance for offspring to inherit the allele. When a male is affected all daughters will be affected but none of his sons. Only 1 copy of the allele is required. Males may be more severely affected

Question 6

Features of X-linked recessive inheritance

Answer 6

Females are usually carriers and males are usually affected (they are hemizygous). For a carrier female; there is a 50% her sons will inherit the disease and a 50% chance her daughters will be carriers. An affected male will transmit the allele to all of his daughters and they will be carriers. No male to male transmission. If a woman is affected; all of her sons will be affected and all of her daughters will be carriers.

Question 7

Penetrance

Answer 7

Fraction of individuals with a genotype who show manifestations of the disease. Analogous to a light swith (can be on or off). There is also age dependent penetrance

Question 8

Expressivity

Answer 8

The degree to which a trait is expressed in an individual. Analogous to a light dimmer. Can be explained in part by sex; environment; stochastic effects; and modifier genes.

Question 9

Sex limitation

Answer 9

Occurs if only one sex can express a phenotype (e.g. unicornuate uterus)

Question 10

Sex influence

Answer 10

Phenotypic expression in some conditions is dependent on an individual’s sex (e.g. gout is more common in males)

Question 11

Stochastic effects

Answer 11

Random effects

Question 12

Modifier genes

Answer 12

Genetic factors outside of the genetic locus causing a disease can be important for the expression of Mendelian diseases

Question 13

Phenocopies

Answer 13

Disease (traits) that are due to non-genetic factors

Question 14

Pleiotropy

Answer 14

Used to describe multiple different phenotypic effects due to mutation(s) in a single gene. Ex. when there are symptoms in skin; nervous system; ocular; etc.

Question 15

Euchromatic regions

Answer 15

More relaxed. Genome sequencing focused here but still not complete.

Question 16

Heterochromatic regions

Answer 16

More condensed; more repeat-rich. Essentially unsequenced

Question 17

How many SNPs are there in each person?

Answer 17

Average of 1 SNP every 1000 bp between any two randomly chosen human genomes

Question 18

What are different regions of the genome?

Answer 18

Gene rich/gene poor; stable/unstable (disease associated); GC-rich/AT-rich (basis for chromosomal banding patterns)

Question 19

What are the two classes of repetitive DNA?

Answer 19

Tandem repeats and dispersed repetitive elements

Question 20

Describe 3 different kinds of tandem repeats

Answer 20

1-in different parts of genome; used for cytogenetic banding 2- a particular pentanucleotide sequence is part of human-specific heterochromatic regions on the
long arms of Chr 1; 9; 16 and Y (hotspots for humanspecific evolutionary changes) 3- alpha-satellite repeats

Question 21

Describe alpha-satellite repeats

Answer 21

171 bp repeat unit near centromeres. May be important to chromosome segregation in mitosis and meiosis

Question 22

Name 2 types of dispersed repetitive elements.

Answer 22

Alu family (eg of SINES-short interspesed repetitive elements); L1 family (eg of LINES).

Question 23

Length and frequency of Alu family

Answer 23

~ 300 bps and 500;000 copies in genome

Question 24

Length and frequency of L1 family

Answer 24

~ 6 kb and 100;000 copies in genome

Question 25

What effect can retrotransition have on dispersed repetitive elements?

Answer 25

May cause insertional inactivation of genes

Question 26

What is another problem we see with repeats?

Answer 26

Repeats may facilitate aberrant recombination events between different copies of dispersed repeats leading to diseases. Non-allelic homologous recombination (NAHR)

Question 27

Name 3 types of human DNA variation (NOT large scale variation; rearrangements; translocations; etc.)

Answer 27

Insertion-deletion polymorphism (indels)(Minisatellites and microsatellites); Single Nucleotide Polymorphisms (SNPs); Copy number variations (CNVs) (Structural variation)

Question 28

Describe minisatellites

Answer 28

tandemly repeated 10-100 bp blocks of DNA. VNTR (variable number of tandem repeats)

Question 29

Describe microsatellites

Answer 29

di-; tri-; tetra-nucleotide repeats; greater than 5 x 104 per genome; A30STRPs (Short Tandem Repeat Polymorphisms)

Question 30

Describe SNPs

Answer 30

frequency of 1 in ~1000 bp; PCR-detectable markers; easy to score; widely distributed

Question 31

Describe CNVs

Answer 31

variation in segments of genome from 200 bp � 2 Mb; can range from one additional copy to many; array comparative genomic hybridization (array CGH); CNV loci may cover 12% of genome; Some CNV regions involved in rapid & recent evolutionary change

Question 32

Describe gene familes

Answer 32

Composed of genes with high sequence similarity (e.g. >85-90%) that may carry out similar but distinct functions; 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)

Question 33

What is the link between CNV regions; human evolution; and human disease?

Answer 33

Such regions are often enriched for human specific gene duplications; enriched for genome sequence gaps; enriched for recurrent human diseases. Ex 1q21.1; 9p13.3-9q21.12; 5q13.3. Link between evolutionarily adaptive copy number increases and increase in human disease (e.g. 1q21)

Question 34

Describe the mechanism linking DUF1220; Brain Evolution and Disease

Answer 34

Increase in DUF1220 copy number -> Possible increase in brain size BUT comes with price of increase 1q21.1 instability. Ex: 1q21.1 duplications associated with macrocephaly and autism. 1q21.1 deletions associated with microcephaly and schizophrenia