Lecture 2: Genetics & Epigenetics

Human Genome Project (HGP)

• intl proj to determine sequence of human DNA & identify human genes

• started in 1990, completed 2003

• sequenced ~3 billion DNA base pairs

• produced 1st reference human genome sequence

why was the HGP important

• gave scientists a foundation for connecting genetic variation → health/disease

• led to advances in:

  • genetic testing

  • personalized med

  • identifying genetic predispositions

important limitations of HGP

• knowing the dna sequence ≠ knowing exactly what everything does

• og sequencing was slow, expensive, & prone to error

• reference genome didn’t represent all human genetic variation

• enviro/lifestyle also influence health

• genomic banks → cybersecurity/re-identification concerns

• genes alone do not determine health

deoxyribonucleic acid (DNA)

genetic storage system of the cell

• contains instructions for making proteins

dna nucleotide

5 carbon sugar, phosphate, & nitrogenous base

• 4 bases:

  • A- adenine

  • T- thymine

  • G- guanine

  • C- cytosine

base pairing

dna is double stranded → double helix

• A ↔ T, G ↔ C

• hydrogen bonds hold the paired bases together

genome

ALL of an individuals dna

• ~3 billion base pairs

exome

protein-coding portions (exons) of the genome

• only ~1-2% of genome

• contains many known disease-related variants

• exome sequencing focuses on these coding regions to look for genetic variants/mutations

whole exome sequencing

sequencing all protein coding regions to look for genetic variants/mutations

• basic process: dna sample → dna fragmented → exons captured/isolated → sequenced → compared/analyzed for variants

genomic info can help

• diagnose genetic conditions

• predict disease risk

• manage/prevent disease

• promote health from preconception →adulthood

big pic: genetics is another tool for pop. level prevention, not j individual diagnosis

genetics in normal ph functions

• surveillance: identify genetic risks in pops

• education: explain genetic risks

• prevention: identify opportunities for earlier intervention

• health services: connect people to appropriate genetic testing/services

• policy: protect people while incorporating useful genomic info

• research: evaluate whether genetic tests are actually clinically useful

gregor mendel

• known as “father of genetics”

• used controlled breeding of pea plants to understand traits being passed between generations

• developed 2 laws

  • law of segregation

  • law of independent assortment

law of segregation

• we carry 2 alleles for a trait

• alleles separate during reproduction

• offpring receive:

  • 1 allele from each parent

law of independent assortment

alleles for unrelated traits can be inherited independently of each other

gene

segment of DNA containing instructions for a functional product

allele

diff version of a gene

dominant

phenotype expressed when 1 copy of allele is present

homozygous

2 identical alleles

• ex: AA or aa

heterozygous

2 diff alleles

• ex: Aa

hemizygous

only 1 copy of a gene is present

• many x-linked genes in XY males

why mendelian genetics doesn’t explain everything

• mendel studied simply binary traits with clear inheritance patterns

• most common human diseases are much more complicated

• often involve:

  • multiple genes

  • enviro

  • behavior

  • other factors

multifactorial trait/disease

• caused by:

  • multiple genes

  • enviro

  • behavior

  • other factors

• ex’s:

  • type 2 diabetes

  • heart disease

  • obesity

ph takeaway: genetic risk ≠ destiny

genetic variation

• differences in dna sequences between individuals

• explains differences in:

  • blood group

  • eye/hair/skin color

• most genetic variation is harmless

• some variants affect health/disease/treatment response

single nucleotide polymorphism

• most common unit of genetic variation

• difference in 1 nucleotide at a particular dna position

• most occur in non-coding dna & have no obvious effect

• some can affect:

  • gene function

  • disease susceptibility

  • med response

SNPs as genetic markers

helps researchers:

• track inheritance

• identify disease-associated regions

• predict genetic predisposition

• study treatment/drug response

variation

• difference in dna

• may b normal & harmless

• not every dna difference causes disease

mutation

• dna change that can disrupt normal function

• may contribute to disease processes

• does NOT mean every dna change is harmful

genome wide association studies (GWAS)

• search across genomes to identify genetic markers

• identify markers associated w particular:

  • traits

  • clinical outcomes

  • compare people w outcome vs. people w outcome

    • look for shared genetic variants

use of GWAS

• understand pop. level disease risk

• can contribute to:

  • personalized meds

  • predicting treatment outcomes

  • understanding shared risk factors/health disparities

important: association ≠ variant directly causes disease

type 2 as a multifactorial disease

• person either clinically has diabetes or does not

• pathway leading to disease can involve:

  • genetic, enviro, & econ factors

• genetics may identify susceptibility

• disease cannot necessarily be explained by genetics alone

BRCA1 & BRCA2

• genes with inherited variants associated with breast cancer risk

• inherited variant ≠ guarantee cancer develops

• only about 5–10% of breast cancer cases are inherited

remember: inherit the mutation, NOT the disease

penetrance

• whether a genetic trait/phenotype appears

• think → will it appear?

expressivity

• degree/severity of the phenotype once it appears

• think → how strongly does it appear?

genotype

individuals genetic makeup/alleles

phenotype

• observable trait or outcome

• can reflect genotype & enviro

• ex’s:

  • weight

  • height

  • eye color

  • disease state

epigenetics

• changes in gene expression

• occurs w out changing dna sequence itself

• dna sequence stays the same

• which genes are ON/OFF can change

important: same genotype ≠ always same gene expression

epigenome

• collection of chemical modifications

• regulates how dna is used

• can be influenced by:

  • development

  • stress

  • aging

  • pollution

  • nutrition

dna methylation

• methyl groups added to dna by methyltransferases

• generally → gene OFF / ↓ expression

• transcription machinery has less access to gene

• can be reversed through demethylation

remember: more methylation → usually less expression

histones

proteins that dna wraps around to help package dna

• how tightly dna is wrapped determines whether genes are accessible

histone acetylation

• enzyme → HAT

• loosens/open chromatin

• dna more accessible

• ↑ gene expression

• remember: acetylation = OPEN/ON

histone deacetylation

• enzyme → HDAC

• tighter/closed chromatin

• dna less accessible

• ↓ gene expression

• remember: deacetylation = CLOSED/OFF

histone methylation

can ↑ or ↓ gene expression

• effect depends on:

  • location

  • context

cell differentiation & epigenetics

• epigenetic changes turn certain genes off/on so cells become specialized

• allows cells to become specialized

• ex:

  • brain cell vs. muscle cell

• essentially same dna → diff genes expressed → diff structures/functions

lifelong enviro epigenetic changes

• cells respond to:

  • diet

  • pollution

  • stress

  • aging

• enviro can modify gene activity over time

• connects enviro → epigenetic change → altered gene expression → potentially altered health

x chromosome inactivation

• occurs in XX individuals

• 1 X chromosome is largely inactivated early in embryonic development

• prevents too much expression of X-linked genes

• called:

  • x-inactivation

  • lyonization

• provides dosage compensation

random x-inactivation

• which X is turned off is generally random in each cell

• once selected → stays turned off

• silencing maintained through later cell divisions

• creates mosaic of cells

  • some use maternal X

  • others use paternal X

xist gene

• key role in X-inactivation

• produces XIST RNGA

• RNA coats X chromosome

• recruits silencing mechanisms

• chromosome becomes largely inactive

• dna methylation helps lock in repression

calico cats

• fur color gene located on X chromosome

• female cat may have:

  • Xᴼ → orange

  • Xᴮ → black

• random X-inactivation →patches of diff colors

• visually demonstrates:

  • random X-inactivation

  • cellular mosaicism

genomic imprinting

• epigenetic process

• expression of an allele depends on which parent it came from

• one parental copy may be silence

• other copy expressed

• mutation can have v diff effects depending on whether inherited from mom v dad

chemical exposures & epigenetics

• environmental exposures can modify gene regulation

• understanding pathways helps ph:

  • identity possible causes of disease

  • advocate for environmental protections/policies

prenatal cig smoke exposure

• major prenatal chem exposure

• cig smoke contains thousands of chemicals including carcinogens

• associated w:

  • prematurity

  • birth defects

  • miscarriage

  • SIDS

prenatal cig smoke & epigenetics

• smoke exposure → altered/reduced dna methylation

• → altered gene expression

• fetal brain research found methylation changes involving neuronal development

connection: exposure → epigenetic change → altered development/disease risk

epigenetic biomarker

• persistent epigenetic pattern

• may provide evidence of a past exposure

• potentially useful when disease occurs years after exposure

potential exposures detected through epigenetic biomarkers

• metals

• pesticides

• benzene

• synthetic hormones

• pollution

ph value of epigenetic biomarkers

• could improve:

  • exposure assessment

  • identification of harmful exposures

  • environmental disease research

  • prevention/policy

idea: past exposure → persistent epigenetic mark → potentially measurable later

teratogen

• substance, agent, or factor that can cause:

  • birth defects

  • developmental abnormalities

• affects a developing fetus