Exam 4 Molecular Biology Dr. Borgon

Humans have how many cells with how many division/day?

~37 trillion cells with 2 trillion divisions/day.

T/F: Mutations can be beneficial, neutral, or detrimental, and cause variation, alter phenotypes, and allow for natural selection.

true

T/F: •They may be somatic or germ line

true

Smaller genomes (viruses, bacteria) typically have a

higher mutation rate

•In humans, a high mutation rate would lead to _____________, a low mutation rate offers _____________

cancer; no variability

The simplest error is a

point mutation, which changes a single nucleotide

Transitions define

-pyrimidine to pyrimidine, or purine to purine (more common). If in the wobble position it only causes 2 of 21 messages (20 aa's, 1 stop) to change

Transversion define

-pyrimidines to purines, purines to pyrimidines. If in the wobble position it causes a change in 12 messages (8 amino acids unchanged)

What are the 5 types of mutations?

-wild type allele
- silent mutation
- point mutation (missense)
-point mutation (nonsense)
- Frameshift

The silent mutation has

no effect

the point mutation (missense) has

amino acid substitution

the point mutation (nonsense) has

stop/truncation

the frameshift has

substitutions, stop/truncation

Point mutations in exons or small insertions/deletions can be

detrimental

Intergenic mutations can affect

regulatory regions and expression

What is an example of insertion?

Pea plants are round (dominant) ]or wrinkled (recessive)

Round seeds have

starch branching enzyme (SBE1) which was lost due to an insertion in wrinkled seeds

What are the mutation rates in RNA viruses?

-RNA: 10-3 to 10-5 per base per generation, often ~1 per genome (ssRNA > dsRNA)

What are the mutation rates in DNA viruses?

-DNA: 10-6 to 10-8 per base per generation

What are the mutation rates in bacteria?

-~1/100th to 1/1000th per generation (1 error in 100-1000 cells)`

Human mutation rates can be studied via

X-linked or dominant mutations, or DNA sequencing of families

What is achondroplasia

dwarfism

Achondroplasia/dwarfism information

•99% from fibroblast growth factor receptor 3 (FGFR3) mutations at position 1138 (new gene mutations only come from father, associated with increasing age, 35+)

Achondroplasia occurs

sporatically during spermatogenesis

What are three examples of where rates can vary 100x or more?

NF1 and DMD and Hungington's DIseases

What is NF1?

Neurofibromatosis type 1

What is DMD?

Duchenne Muscular dystrophy

What mutation rate is associated with NF1 and DMD?

1 * 10^-4

What mutation rat is associated with Huntington's Disease?

1 * 10^-6

In human mutation rate, there are _____ mutations per _________ base pairs per year mutation rate

0.5; billion

In human mutation rate, there is _____ mutation per ______ million bp per generation (100-200 total), most or all in noncoding region

1; 30

•, JBS Haldane (one of the founders of genetics) predicted that we each have

~100 new mutations

From cell division to cell division, the error rate for DNA polymerase combined with other repair enzymes is about _____ mistake in _______________ base pairs copied

1; 1 billion

. At this rate, there are about _____ mistakes with each diploid cell replication event.

6

Children have ___________ differences from parents

100-200

Eggs only undergo _______ replications, whereas sperm stem cells divide once every ______ days

23;16

Therefore the male germline is more/less mutagenic due to more cell divisions, increases with age?

more

In DMD, 93% of point mutations were

paternal

In DMD, 87% of deletions were

maternal

You are still different from each parent by hundreds of ________________________ of bases

hundreds of thousands or million

One study showed more male mutations: A group analyzed DNA taken from 85,289 Icelanders

found 3.3 paternal germline mutations fo r each maternal mutation

A second study showed high variability: 92% of mutation were _________, 64% __________ in different families

paternal; maternal

•Studies support __________ mutations per generation

100-200

Overall they found _________ damaging variants and ___- disease mutations per individual

400;2

•Mutations assort _________________ and some are removed each generation with new ones being added, maintaining ~_______ mutations each

independently; 300

Mosaicism define

-Many mutations are post-zygotic, not germline, and are present in only some of your cells. Some cells have more than one genotype due to errors, resulting in different tissue types. This is why we go back to a single cell for reproduction

What is uniparental disomy?

When some children get more genes fromn one parent due to a duplication after the first cell division

Microchimerism define

-Cells from fetus can remain in womb, pass to future children

What is an example of microchimerism?

-Mothers/children share immune cell lines, and Y chromosome cells found in mothers (brain, skin, liver, spleen) who had sons

Chimerism define

-Fraternal twins fuse to develop into one person

What are two examples of chimerism?

-Females with Y chromosomes in their body (first found when testing athletes), or people with two different blood types
-Several women have been told they aren't the mother of their children based on DNA evidence. Both women had two different sets of chromosomes in various body parts, including their ovaries

•We are all very closely related (99.9%), and there is genetic evidence of

multiple bottlenecks

-Alu sequences show the human population size was less than __________ at 1.2 million years ago

26,000

Due to the Toba catastrophe theory

-70,000 years ago humans were reduced to 1,000-10,000 individuals

-Male (but not female) bottleneck 4,000-8,000 years ago, possibly due to

wealth/power/war

The common ancestor of everyone alive today very likely lived between

2000 to 5000 years ago.

•Mitochondria and the Y chromosome can be used to

analyze genomes and map ancestry

-Mitochondria mutate once every 300-600 generations (6000-12,000 years), and it can be used as

a molecular clock

-Some species such as the transcaucasian mole and spiny rat

have lost their Y chromosomes and have no SRY gene

The Mitochondrial and Y chromosome lineages each lead back to a single ancestor

mitochondrial Eve ~200,000 years ago, Y Chromosomal Adam ~200,000-300,000 years ago

•Mutations are typically found in

<1% of population

•SNPs are more common,

found in >1% of population

SNPs are the source of many

alleles

All mammals are ______% genetically identical, and humans are ________% identical

92;99

SNPs occur in _____% of genome, 1 every ~_______ bp, account for __________% of differences between humans

1;300;80-90

Sesquizygous define

fraternal twins from a single egg and 2 sperm ~75% identical

Uniparental disomy

two chromosomes from one parent

What is the relatedness of great-grandparents?

12.5%

What is the relatedness of grandparents?

25%

What is the relatedness of great uncle and aunt?

12.5%

What is the relatedness of parents?

50%

What is the relatedness of uncle or aunt?

25%

What is the relatedness of first cousin once removed?

6.25%

What is the relatedness of sinblings?

50%

What is the relatedness of self?

100%

What is the relatedness of first cousin?

12.5%

What is the relatedness of second cousin?

3.13%

What is the relatedness of niece or nephew?

25%

What is the relatedness of child?

50%

What is the relatedness of first cousin once remove\d?

6.25%

What is the relatedness of second cousin once removed?

1.56%

T/F: Introns/intergenic DNA: may/may not have an impact

true

Example of introns/intergenic DNA

TF binding, expression levels, splicing, miRNAs

T/F: Exons: may/may not have an impact

true

Examples of exons

mutation, or no effect on protein due to degeneracy of the code

For example, there are thousands of hemoglobin variants: some cause

disease, influence levels, or no effect, many SNPs associated with pathogen resistan

Six examples of SNP

Alzheimer's Disease
Sleep
Pain
Coffee Consumption
Speed dating
Cold adaptation

Alzheimer's Disease

apolipoprotein E (ApoE) contains two SNPs that result in E2, E3, E4 alleles. E4 associated with increased risk of disease, E2 a lower risk

Sleep

•BHLHE41 (basic helix-loop-helix) has multiple variations that prevent proper circadian clock transcription factor interactions allow some people to only need six hours of sleep per night

Pain

woman feels no pain due to a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, and a SNP conferring reduced expression

Coffee consumption

•: two single nucleotide polymorphisms near CYP1A2 and AHR genes were correlated with increased coffee consumption, those with the SNPs consumed an extra 40 mg of caffeine per day

Speed dating

SNPs in the opioid and serotonin receptors predicted speed-dating success for women and men, respectively. Dampening effect if found in the opposite gender

Cold adaptation

•SNP upstream of the only cold receptor gene TRPM8 (an ion channel, bound by menthol) has a distribution range, from 5% in Nigeria to 88% in Finland. Has also been linked to migraines (higher in Europeans)

What does lactase do?

breaks down lactose in milk.

when does lactose increase?

increases in the 3rd trimester, decreases after age 5

what percent of the world has decreased lactase levels?

75% of the world

but 95% of who can completely tolerate lactase levels?

northern Europeans

7500 years ago in European dairy farmers, a TàC change occurred ____________ of the lactase gene

upstream

the lactase gene was in an intron of ________ (helicase) which is bound by __________ enhance and results in a 2.8x lactase inc rease

MCM6; Oct1

What survival advantage did this give?

consume fresh milk
increase serum calc ium
increase bone density