Human Genetics Exam 1 (Counterman)

Central Dogma

DNA(replication)->RNA(transcription)->Protein(translation)

Simple genetic basis

single gene/locus/mutation

Point mutation

single nucleotide mutation

Indel mutation

leads to frameshift mutation

Inversion mutation

centromete flipped upside down, common

Insertion mutation

1 chromosome inserts into another

Duplication mutation

duplication of a region of DNA on the same strand

Mutations effect:

Structure, function, protein, fitness

Effect on structure

Hemophelia A: inversion of F8 gene

Loss-of-Function mutation

causes a complete or partial loss of function, usually recessive

Gain-of-Function mutation

ie 2 wings mutate into 4 wings

Lethal function mutation

usually during early embryonic failure of genes involved in mitosis

Frameshift mutation

effect the creation of a protein

Deleterious fitness effect

neg effect on fitness (most common)

Neutral fitness effect

almost no effect on fitness

Adaptive fitness effect

fitness advantage

Ne

actual population that is able to create the next generation

New population

population in embryonic development

Most common fitness effect?

Neutral

Most common fitness effect on new populations?

Lethal

Exon

nucleic acid sequence that represents mature RNA

Intron

any nucleotide sequence with a gene that is removed to make the final mature RNA

Gene

unit of heredity, the actual DNA sequence that codes for proteins

Genome

all of the genetic information or hereditary material in an organism

Gene/locus

multiple definitions:

1. part of the genome

2. uses amino acids to make proteins 3. uses regulatory elements (when to turn on)

Allele

1 or two or more possible forms of gene (locus)

Polymorphism

presence of multiple forms in natural populations (beach mice v forest mice)

SNP (single nucleotide polymorphism)

site in genome with more than one nucleotide base present in population

actctaGctata

actctaCctata

Genotype

specific allelic composition of a cell

Haplotype

single genomic copy

Continuous trait

varies with a wide range, often with normal distribution

Discontinuous trait

dichotomous trait, often binary

Histogram

a bar graph depicting a frequency distribution

Normal Distrubution Curve

sample size of 30, bell curve

Lower frequency symbol

q

Higher frequency sympol

p

Hardy-Weinberg equation

p^2 + 2pq + q^2 = 1

nonsynonymous mutation

A mutation in a gene that changes the amino acid sequence of the protein that gene encodes.

Intergenic

desert of genes

synonymous mutation (silent)

A mutation that does not result in a different amino acid

Genetic architecture steps:

1. how many genes/loci involved?

2. size effect distribution of alleles?

3. How do these genes interact?

4. What other traits do these genes impact?

5. Is a single locus affecting 2 or more phenotypes?

Mendellian trait

a trait completely determined by a single gene (simple genetic basis)

Size effect distribution

ie impact on height if gene affect legs v no legs compared to the impact on height if gene affect head length

Additive genetic model

1% increase, so need many to have a big impact

Epistasis

interaction between 2 loci

Pleiotropy

The ability of a single gene to affect multiple phenotypic traits.

Simple traits

Hair color, eye color

Human Genome

3.2 billion base pairs

Gene density in mitochondrial genome

One per 1 kb

Gene density in nuclear genome

One per 100 kb

Gene size

~27 kb, but enormous in variation

How many genes in the human genome?

24K

Genetic architecture for eye color

1. Single locus with 2 genes

2. HERC2 contains OCA2:effecting expression (epistasis)

3. 8 other genes add to variation (small)

Generic architecture for hair color

1. Mc1r gene controls major variation

2. Red hair evolved from 4 mutations

3. 8 other genes influence red hair

Human Gene Regulation

1. What is transcribed

2. When and where

Promoter

A short motif protein recognizes to bind RNA poly to DNA

Transcription factors (TFs)

regulatory proteins that respond to a signal & bind to specific DNA sequences near a gene

General TF

Involved in turning on every single gene (TBP)

Specific TF

Only present at specific time and place (SRY)

TATA box

Core promoter (on/off switch)

Proximal promoter

Enhancers and silencers

How many TFs in human genome?

1500

What % of genes have TATA box?

25%

Methylation of Histone Tails

Signal that chromatic should be closed (state associated with marks)

Acetlyation of histone tails

Less positive charge makes open chromatin(state shown w marks)

H3K9ac

Histone 3, Lysine 9, acetylene

H3K4me

Histone 3, Lysine 4, methylene

Faciltative (H3K27me3)

Closed but CAN open

Constitutive (H3K9me3)

Never open (centromere)

Epigenetics in Normal Regulation

1. Gene body open/closed

2. Genes upstream/downstream determine open/closed

3. Many factors affecting gene on/off

How do transcription factors affect chromatin?

Can open it to make TATA box accessible

How do TFs alter the Histone code?

They recruit proteins (blobs)

What are 4 main ways to find regulatory elements?

1. ATAC-seq

2. RNA-seq

3. CHIP-seq

4. HI-C

How do TF recruited proteins (blobs) alter Histone code?

Readers, writers, erasers

ATAC-seq (expensive)

fragmented DNA with magnet tags produce peaks showing everywhere open/closes chromatin

p arm

short arm of chromosome

q arm

long arm of chromosome

Sanger sequencing (small scale)

1. PCR

2. Size separation by gel

3. Laser excitation

What makes up most of the human genome?

transposable elements (unknown function)

What is the smallest part of the human genome?

Genes

What was studied to provide gene annotation?

Model organisms

Disease associated alleles

Lots that do a little but collectively do a lot

Stability of mRNA

Extremely unstable, VERY sensitive to mRNAse

What does a peak represent in RNA-seq?

Evidence of where we have gene expression across genome

RNA-seq

Antibodies attached to fragmented cDNA (tags) which is then released and sequenced

ChIP-Seq

Chromatin antibody binding to methyl tags followed by DNA sequencing

What do peaks represent in CHIP-seq?

Methyl tags

Hi-C sequencing

How close pieces of DNA are to each other to find 3D structure of DNA

Neo-Lamarckism

inheritance of acquired characteristics

Mutationism

discrete variations are all that matter

What did Mendelian genetics disprove?

Lamarkian genetics

Ronald Fisher

Father of statistical genetics

Haldane

Theory of gene frequency

Early genetics impact on human society

Better agriculture, Eugenics

Eugeneics

selective breeding of humans

Margaret Sanger

Planned parenthood

Buck v Bell

1927 supreme court decision that upheld a state eugenics law. The law had allowed for sterilization of the "feeble-minded"

Never been reversed

Impact of Buck v Bell

50,000 Americans nonconsensual sterilization

criticisms of evolutionary psychology

Doesn't address human complexity and fails to explain theories