Human Genetic Variation

WeibinShi

Genetic variations underlie

phenotypic differences
Wilt Chamberlain,
a famous NBA basketball player
(7 feet, 1 inch; 275 pounds)

Willie Shoemaker,
a famous horse racing jockey
(4 feet, 11 inches;
barely 100 pounds).

Genetic variations cause

inherited diseases

Genetic Diseases

Complex Diseases

Environmental
Diseases

- Cystic fibrosis

- Alzheimer disease

- Influenza

Downsyndrome

- Cardiovascular
Disease

- Hepatitis

- Sickle cell disease

- Turnersyndrome

- Diabetes (type 2)

- Measles

- Parkinson Disease

- Environment

- Genes

Basic terminology

Locus location of a gene/marker

on the chromosome.

Allele one variant form of a

gene/marker at a particular locus.
Locus1
Possible Alleles: A1,A2
Locus2
Possible Alleles: B1,B2,B3

A
little
more
basic
terminology
Polymorphism:
Polymorphism:

Variations in DNA sequence (substitutions, deletions,

insertion, etc) that are present at a frequency greater
than 1% in a population.
Have a WEAK EFFECT or NO EFFECT at all.
Ancient and COMMON.

Mutation:

Variations in DNA sequence (substitutions, deletions, etc) that

are present at a frequency lower than 1% in a population.
Can produce a gain of function and a loss of function.
Recent and RARE.

Some Facts

In human beings, 99.9% bases are same

Remaining 0.1% makes a person unique

Different attributes / characteristics / traits

how a person looks
diseases he or she develops

These variations can be:

Harmless (change in phenotype)

Harmful (diabetes, cancer, heart disease, Huntington's
disease, and hemophilia )
Latent (variations found in coding and regulatory regions, are
not harmful on their own, and the change in each gene only
becomes apparent under certain conditions e.g. susceptibility
to heart attack)

Forms of genetic variations

Single nucleotide substitution: replacement of
one nucleotide with another
Microsatellites or minisatellites : these tandem
repeats often present high levels of inter- and
intra-specific polymorphism
Deletions or insertions: loss or addition of one
or more nucleotides
Changes in chromosome number, segmental
rearrangements and deletions

How many variations are present

in the average human genome ?
SNPs appear at least once per 0.3-1-kb average intervals.
Considering the size of entire human genome (3.2X109 bp),
the total number of SNPs is around to 5-10 million
Potentially polymorphic microsatellites are over 100,000 across
the human genome
The insertion/deletions are very difficult to quantify and
the number is likely to fall in between SNPs and microsatellites

How do we find sequence

variations?
look at multiple sequences
from the same genome region

use base quality values to decide if

mismatches are true polymorphisms or
sequencing errors

Vcam1 : Coding-NonSynonymous
AGGAAAAGAACATAACAAGAACTATTTTTCGCCCGAACTC B6
AGGAAAAGAACATAACAAGGACTATTTTTCGCCCGAACTC C3H

B6

C3H

Human Genetic Variation

Most abundant type:
SNPs-Single Nucleotide Polymorphisms
GATTTAGATCGCGATAGAG
GATTTAGATCTCGATAGAG

about 90% of all human genetic variations

What is the difference between

SNP and mutation?

For a variation to be considered a SNP,

it must occur in at least 1% of the population.

Life cycle of SNP

(long way from mutation to SNP)
Appearance of
new variant
by mutation

Survival of rare allele

Increase in allele frequency

after population expand
New allele is fixed
in population
as novel polymorphism

Basic facts about SNPs

SNPs occur every 300-1000 bases in human genome;

Two of every three SNPs involve the replacement of

cytosine (C) with thymine (T);

SNPs can occur in both coding (gene) and noncoding

regions of the genome;

Many SNPs have no effect on cell function, but others

could predispose people to disease or influence their
response to a drug.

Single base changes

Transitions

Purine to purine or pyrimidine to pyrimidine

A to G or G to A T to C or C to T

Transversions

Purine to pyrimidine or pyrimidine to purine

SNP Databases
NCBI dbSNP
http://www.ncbi.nlm.nih.gov/SNP/index.html
Human Genome Variation Database (HGVbase)
http://hgvbase.org/
InternationalHapMapProject
http://snp.cshl.org/

Classification of SNPs

1. Coding SNPs

Synonymous: when single base substitutions do not

cause a change in the resultant amino acid
Non-synonymous: when single base substitutions
cause a change in the resultant amino acid

2. Non-coding SNPs that influence gene

expression

3. Non-coding silent SNPs

SNPs as gene mapping markers

SNPs are used as genetic markers to identify
genes responsible for disease susceptibility
or a particular trait.

Point mutations

Not all single base pair differences are SNPs

They can be a mutation if least abundant allele has

a frequency < 1% in a population

Causes of gene mutations

Consequences of mutations
Most mutations are neutral

97% DNA neither codes for protein or RNA, nor indirectly

affects gene function
A new variant in the 1.5% coding regions may not result
in a change in amino acid
Variants that change amino acid may not affect function

Certain mutations have functional effect

and even cause disease

Gain-of-function mutations often produce dominant

disorders
Loss-of-function mutations result in recessive disease

Consequences of mutations

Missense mutations differ in severity

Nonsense mutation results in premature

termination of translation

conservative amino acid substitution substitutes

chemically similar amino acid, less likely to alter function
nonconservative amino acid substitution substitutes
chemically different amino acid, more likely to alter
function
consequences for function often context-specific

truncated polypeptides often are nonfunctional

Point mutation in non-coding region may affect

transcription, RNA splicing, and protein assembling

Microsatellite
di-, tri-, and tetra-nucleotide repeats
TGCCACACACACACACACAG
TGCTCATCATCATCAGC
C
TGCTCATCA------GC
TGCCACACACACA-----TGCTCAGTCAGTCAGTCAGGC
GC
TGCTCAGTCAG--------GC
The second abundant genetic variation in the human
genome
Usually have no functional effect, but some do

Trinucleotide repeats-associated
diseases
Characterized by expansion of three-

base-pair repeats

few repeats to hundreds of repeats

expansion results in abnormal protein, disease
number of repeats may expand in subsequent
generations

Triplet repeat expansion

Normal

Huntington disease
Kennedy disease

Disease

Gene

CAG 9-35 37-100

Huntingtin
CAG 17-24 40-55 androgen receptor

Spino-cerebellar Ataxia CAG 19-36

Machado Joseph D
CAG 12-36
Myotonic dystrophy
CTG 5-35
Fragile X
CGG CCG GCC 6-50

43-81
67-75
50-400
200-1000

Ataxin 1
SCA

DM
FMR1

Manyresultinneurodegeneration
Severityofmanydiseasesincreaseswith
thenumberofrepeats

Minisatellite
6-64 bp repeating pattern
1tgattggtctctctgccaccgggagatttccttatttggaggtgatggaggatttcagga
61attttttaggaatttttttaatggattacgggattttagggttctaggattttaggatta
121tggtattttaggatttacttgattttgggattttaggattgagggattttagggtttcag
181gatttcgggatttcaggattttaagttttcttgattttatgattttaagattttaggatt
241tacttgattttgggattttaggattacgggattttagggtttcaggatttcgggatttca
301ggattttaagttttcttgattttatgattttaagattttaggatttacttgattttggga
361ttttaggattacgggattttagggtgctcactatttatagaactttcatggtttaacata
421ctgaatataaatgctctgctgctctcgctgatgtcattgttctcataatacgttcctttg

Theseoccuratmorethan1000locationsinthehumangenome
Usuallyhavenofunctionaleffect

Transposon and mutation

TransposonsareinterspersedDNArepeatsthatcancausemutationsand
changetheamountofDNAinthegenome

Nondisjunction

Trisomy

Trisomy 21
Down Syndrome

Down Syndrome

1 per 800 births

Large tongue
Flat face
Slanted eyes
Single crease
across palm
Mental retardation

Some are not

Turner Syndrome

Turner Syndrome

Short
Absence of a
menstrual period
Produce little
estrogen
Sterile
Extra skin on neck

Polymorphism

Mutation

Gene confers an increased

risk, but does not directly
cause disorder

Mendelian pattern of
inheritance

No clear inheritance pattern

Rare

Common in population

Gene directly leads to

disorder