Identifying Mendelian Disease Genes

Question 1

regions of chromosomes which tend to have recombination events
• each chromosome goes thru on average one recombination event per chromosome arm

Answer 1

recombination hotspots

Question 2

this involves separating maternally and paternally inherited copies of each chromosome into haplotypes (a physical grouping of genomic variants (or polymorphisms) that tend to be inherited together) to get a complete picture of genetic variation, tells us which chromosome each of the variants is found on

Answer 2

Phasing

a haplotype is a genotype that has been phased

Question 3

is a physical grouping of genomic variants (or polymorphisms) that tend to be inherited together
typically reflects a unique combination of variants that reside near each other on a chromosome
is a genotype that has been phased - i.e. assignment of SNPs or alleles to parental chromosomes

Answer 3

haplotype

Question 4

regions between recombination hotspots are called?
material here is inherited together and not shuffled thru meiosis over many generations - genetic material here is tightly linked

Answer 4

halotype blocks

Question 5

what do we learn from identifying haplotypes?

Answer 5

A haplotype- contains information about the phasing
could determine which versions of each SNP are on the same chromosome, and therefore which set was inherited from each parent.

Important to know which parent could have contributed to the SNP causing a disease - then can correlate to phenotypes shown

Question 6

the exception to the law of independent assortment relating to linkage

Answer 6

all genetic traits are inherited independently except those that are linked

Question 7

the tendency for any two variants/alleles near each other on the same chromosome to be inherited together
• recombination determines linkage
‣ bc recombination is the only way to separate units on a chromosome
‣ the more common recombination occurs bt two loci, the less tightly they are linked, closer variants are generally the more tightly linked
• the linkage bt two loci is a measure of how frequently recombination occurs bt them during meiosis

Answer 7

Genetic Linkage

Question 8

what is recombination frequency RF?

Answer 8

recombination frequency is the % of meoises in which recombination separates 2 loci
highest value is 50% - and that is random assortment
given in centimorgans (cM)
1% = 1cM

Question 9

describe the two scenarios of unlinked variants on chromosomes

Answer 9

1. if two variants are on different chromosomes they are unlinked
2. if they are far apart on same chromosome so that recombination will separate them 50% of the time they are unlinked

Question 10

describe the scenario of linked and tightly linked variants on chromosomes

Answer 10

if they are close on the same chromosome and recombination separates them less than 50% of the time they are linked

many neighboring genes are tight linked (bc rarely separated by recombination)

Question 11

how can the idea of Linkage be used to identify disease genes in the human genome?

Answer 11

This approach is based on the idea that the affected individuals in a family will all have inherited the same allele of a disease gene, and along with it, the regions that are linked to it. By identifying those regions, which are identical by descent in the affected family members, it is possible to narrow down the location of a disease-causing variant.

We can use Linkage analysis

Question 12

analysis to narrow down possibilities for genetic disease by mapping out the genetic region where the gene is found

• SNP markers can be used to identify genomic regions that are identical by descent in affected individuals but not the unaffected individuals in a family; this identifies the genomic region containing the disease-causing allele.

Answer 12

Linkage analysis

To do linkage analysis:
• conducted using sequence specific markers (SNPs) across the genome
• look at SNPs from both parents to see which passed along the disease
* identify the disease variant - narrow down region where it is located

Question 13

When trying to identify the variant that causes a condition, there will often be multiple candidates. All candidate variants must be classified on a spectrum bt benign and pathogenic based on the likelihood of causing the condition. What are ways to identify the variant by- sequencing?

Answer 13

from targeted to broad:

variant-specific testing- done when the specific variant is known to be causative of the condition
* have to sequence small region (about a base) ex: sickle cell anemia

gene specific testing- looking at a single gene (abt 1-10 kb) ex: phenylketonuria

targeted gene panel- (abt 1 million bases) ex: hereditary cancer, cardiac disease

whole exome sequencing- looking at just the exons (45 MB)
and whole genome sequencing -( 3gb)
* both will give you a lot of variants

Question 14

After you identify variants from sequencing, what approach do you use to narrow it down to get to the variant that causes the disease?

Answer 14

A. each variant is assigned on scale from benign to pathogenic
* comes from evidence from gene, variant, and population level

‣ gene level - gene function is unrelated to condition (benign) or other variants in gene cause condition (pathogenic)
‣ variant level- unlikely to disrupt protein function/levels (benign) or likely to disrupt protein function/levels (pathogenic)
‣ population level [IMPT one] - common in healthy individuals (benign) or found in people with condition (pathogenic)