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GGE > Genetics 5 - Haplotypes and Consanguinity > Flashcards

Genetics 5 - Haplotypes and Consanguinity Flashcards

1
Q

learning outcomes

A
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2
Q

gene

what is the determinant

A

a biological determinant of a Mendelian character (trait)

a functional unit of DNA is now understood to be that determinant

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3
Q

haplotype (haploid genotype)

A

set of polymorphisms (set of polymorphic genes = alleles OR set of genetic markers = SNPs) that are grouped tightly together on a single chr and tend to be inherited together through many generations (not separated by crossing over)

can refer to a combination of alleles or to a set of single nucleotide polymorphisms (SNPs)/genetic markers

also known as a DNA/genetic signature

chunk of chr (crossing over)

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4
Q

haplogroup

A

group of similar haplotypes that share a common ancestor with a SNP mutation

e.g. mtDNA haplogroups (7 daughters of Eve) share common SNPs in mtDNA

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5
Q

white eye colour on fruit fly drosophila

A

linked to X chr

⇒ genes were linked - carried on specific chromosomes and inherited together

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6
Q

why are some “linked” genes not inherited together

A

crossing over

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7
Q

first chromosomal linkage map ⇒

A

genes more closely grouped on chromosomes were separated less frequently by crossing over

closely linked genes (e.g. vermillion eyes and miniature wings were more likely to belong to the same haplotype (chunk)

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8
Q

how to show linkage of a haplotype to a character

A

examine haplotypes of related individuals with the same traits

if they have a haplotype in common, we can assume that the gene responsible for the shared trait is in that area

UNKNOWN - which part of genome we need to focus on - comparing all the genes is very difficult

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9
Q

human nuclear genome - what do we know

A

lots of noncoding sequences - 98%

including tandem (head to tail) repeats

interspersed repeats (throughout genome i.e. not head to tail, may be on different chromosomes

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10
Q

define tandem repeat

A

series of nucleotides directly repeated

length of repeat unit varies

can be used as genetic markers for identification of haplotypes

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11
Q

satellite DNA (type of tandem repeat)

size

use

A

very large arrays of non-coding tandemly repeating DNA

array of 100 kb - several Mb (this is the total size of repeat units put together)

length of repeat unit > 100 bp

sequences vary between individuals

undefined role in cell cycle - used in DNA fingerprinting

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12
Q

minisatellite DNA (type of tandem repeat)

size

use

A

medium size

array from 10 bp up to 20kb

length of repeat unit = 10-100 bp

high mutation rate, high diversity in population - VNTR (Variable Number of Tandem Repeats) ⇒ the more it mutates, the more it repeats, the more common it is that the mistake will happen

used for variable tandem repeat analyses

found in subtelomeric region of chr ⇒ protects chr ends from damage

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13
Q

microsatellite DNA (type of tandem repeat)

size

use

A

simple sequence repeats (SSR) or short tandem repeats (STR)

arrays of less than 100 bp

length of repeat unit typically 2-4bp

used in genetic linkage analysis to locate a gene or a mutation responsible for a given trait or disease

MOST COMMON

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14
Q

3 types of tandem repeats

A
  1. satellite DNA
  2. minisatellite DNA
  3. microsatellite DNA
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15
Q

where is microsatellite DNA found

how much of genome does it account for

type of sequences

A

dispersed throughout chr

accounts for about 2% of genome (60 Mb)

microsatellites usually in intergenic sequences or introns

sometimes in coding sequences (exons)

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16
Q

microsatellites in exons

A

tend to be mutation hot spots

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17
Q

instability of microsatellite DNA

A

during replication DNA polymerase tends to make errors in copying repeated units - due to their similarity

e.g. may skip over a repeat unit or copy it twice

because replication of repeat units is very error prone microsatellite DNA sequences are highly polymorphic (many different forms)

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18
Q

microsatellite polymorphism

A
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19
Q

other type of microsatellite polymorphism - SNPs

where does it occur

A

occurs upstream of a microsatellite

SNP in Man 1 will not be apparent if the PCR products are analysed only by size, only becomes apparent if you sequence

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20
Q

SNP vs microsatellite polymorphism

A

microsatellite polymorphisms - look at size

SNP - need to know sequence

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21
Q

using microsatellite DNA as a marker for tracking

A

suppose human genome databases show a microsatellite (trinucleotide repeat CTT) in intron 2 of gene X on chr 1

can use genome database to design complementary oligonucleotide primers upstream (5’) and downstream (3’) of this microsatellite sequence - flanking sequence

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22
Q

functions of microsatellite sequences as markers

A

design primers

determine appropriate conditions (annealing) for amplification

extract DNA from patient

amplify the interval between the primers

get PCR products

measure size of PCR product

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23
Q

microsatellite sequence - what fills in the gaps

A

DNA polymerase

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24
Q

based on size of PCR product, what can you determine

A

how many repeats or what you’re microsatellite no of repeats is

Primers = 20 nucleotides each

In between is the rest

64 - 20 = 44 24 bps

Each of bp is 3 nucleotides

24 divided by 3 = 8

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25
Q

equation for no of repeats

A

Size of primer + size of amplified microsatellite sequence in between and divide by no of nucleotides in a repeat unit = no of repeats

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26
Q

tracking chromosomes or chunks of chr

A

using microsatellites and SNPs you can construct a “barcode” for each Chr or chunk of chr (haplotype)

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27
Q

linkage

A

relationship between loci

specifically genetic phenomenon

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28
Q

linkage analysis

A

looks at physical chunks of the genome (haplotypes) of related individuals and associates them with given traits

29
Q

how are trait causing mutations inherited

A

jointly (linked) with the genetic markers (i.e. microsatellites and SNPs) located in their immediate vicinity on the same chromosomal strand

30
Q

principle of linkage analysis

A

if we find a common genetic marker (e.g. microsatellite or SNP), we assume that the gene that causes the disease is somewhere in the same area

31
Q

how to identify trait-related haplotype (chunk)

A

perform genetic analysis of polymorphic DNA markers associated with the trait for all family members

can use the dbSNP database to find appropriate markers

see which markers are carried only by members with the trait

high probability (odds) that trait causing gene is linked to this marker (same location on chr)

32
Q

red hair as a recessive trait

A
33
Q

what pattern would Hermione show

A
34
Q

things to remember

A
35
Q

learning outcomes

A
36
Q

consanguinity

A

being descended from the same ancestor as another person

8.5% of children worldwide - consanguinous parents

endogamy is widely practised in Middle East

37
Q

clinical definition of consaguinity

A

matrimony (breeding) between 2 family members who are 2nd cousin or closer

associated with increased risk of autosomal recessive disorders

38
Q

risks associated with consanguinity

A

increased risk of genetic disease from 2 → 4%

probability of having a child without a constitutional congenital defect reduced from 98% → 96%

39
Q

this pedigree is suggestive of what pattern of inheritance

A

autosomal recessive deafness

(Do the parents carry it? No - recessive

If females have it, it is unlikely to be X linked)

40
Q

autosomal recessive deafness accounts for

A

65% of congenital deafness

infection is also important

41
Q

syndromic vs non-syndromic deafness

A

syndromic - part of another condition

42
Q

4 patterns of inheritance of deafness

A

dominant (DFNA) - 20-25%

recessive (DFNB) - 75-80%

X-linked (DFNX) - 1-2%

matrilineal (mitochondrial) - <1%

43
Q

autosomal recessive patterns of inheritance are related to

A

homozygous state for a defective allele

44
Q

assumption for inherited deafness

A

likely there is an inherited determinant of deafness in the family - bad gene

mapping is about finding the DNA sequence that corresponds to this gene

45
Q

common genes for hereditary deafness

A

single locus - DFNB1 (13q) accounts for a high proportion

GJB2 (connexin 26 protein)(Cx26) - 2 exons ⇒ amplification and sequencing is practical

c. 35delG - common in Europeans
c. del235C - common in Chinese

46
Q

after looking for common mutations, what is next

(> 100 genes known associated with hereditary deafness - almost impossible)

A
47
Q

basic hypothesis

A

Nasreen has ended up with 2 copies of GGF’s defective chr 1p

48
Q

if it was simple what should all 3 deaf individuals have

A

2 practically identical copies of relevant ancestral chr that carries the defective allele or bad gene

however, crossing over between maternal and paternal means that many offspring do not inherit a full intact version

should all be homozygous for a particular chunk (haplotype) of ancestral chr that carries the defective allele

49
Q

how to identify deafness-related haplotype by linkage analysis

A

perform genomic analysis of polymorphic DNA markers associated with deafness for all family members

see which markers are carried only by deaf members and never healthy members (segregate with the disorder)

high probability that deafness causing gene is linked to this/these marker(s) - same location on chr

50
Q

autozygosity mapping

A
  1. identify microsatellite sequences associated with deafness loci using dpSNP database
  2. amplify DNA from all of the loci of all family members
  3. determine the size of PCR products in each individual - affected individuals should all be homozygous for the same haplotype (set of markers)
51
Q

microsatellite locus for Nasreen and her 2 deaf uncles

A

single products suggests that they are all homozygous for a particular chr 2 haplotype with the same no of repeats (13) at that specific micro-satellite locus

may have 2 copies of an ancestral chr 2 from a specific grandparent

MUMTAZ MAY HAVE 2 DIFFERENT PRODUCTS (heterozygous)

  1. a 99bp product - ancestral chr 1
  2. maybe an 81 bp product (7 repeats) from the corresponding locus on the other chr 1 homolog
52
Q

where is the affected deafness allele located

A
53
Q

defective allele for inherited deafness

A

chr 2 haplotype - a chunk of chr on short arm (p) of chr 2

defective allele is in p22-p23 region of chr 2

deafness associated locus there = OTOF (otoferlin) - 2p23.3

54
Q

9th indentified type of autosomal recessive non-syndromic hearing loss

A

DFNB9

55
Q

association is not causation re

A

linkage of a trait with a gene/DNA sequence associated with the disorder is not always important in the pathogenesis of the condition

deafness associated locus was OTOF - 2p23.3 and not it’s linked microsatellite marker

56
Q

Coeffecient of relationship (COR) (Sewall Wright)

A

proportion of alleles that 2 people share by virtue of having 1 or more definable common ancestors

57
Q

coefficient of inbreeding (COI)

A

proportion of loci at which the person is expected to be homozygous because of the cansanguinity of the parents

OR

the probability that at any given locus the person receives 2 alleles that are identical by descent

COI = half the coefficient of relationship of the parents

58
Q

outbred calculation of COR - parents

A

share 50% of alleles with their children

59
Q

outbred calculation of COR - full siblings

A

50%

60
Q

outbred calculation of COR - grandparents

A

share 25% with grandchildren

61
Q

outbred calculation of COR - uncle/aunt

A

share 25% with niece/nephew

62
Q

outbred calculation of COR - cousins

A

12.5%

63
Q

allele frequency

A

incidence of a gene variant in a population

number of times the allele of interest is observed in a population/total number of copies of all the alleles at that locus in the population

reflection of genetic diversity

64
Q

allele frequency does not ⇒

A

NOT THE SAME as saying 40% of the population have a copy of the allele

e.g.

10% of 100 people are homozygous for allele R1 (20 copies)

20% are heterozygous for allele R1 (20 copies)

allele frequency = 40/200 = 20%

65
Q

Hardy-Weinberg Equilibrium

assumptions

A

allele and genotype frequencies in a population will remain constant from generation to generation in the absence of other evolutionary influences

alleles distributed randomly only under certain assumptions including the absence of selection and random mating (a panmictic population)

p2 + 2pq + q2 = 1

p + q = 1

66
Q

e.g. Hardy-Weinberg Equilibrium

A
67
Q

e.g. Hardy-Weinberg Equilibrium

A
68
Q

things to remember

A

GGE (33 decks)

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