5/4/15

Week of 5/4 - last Discussion, last homework

- Discussion sec9on grades will be normalized to class average

Tues 5/5 - Lecture 24
Thurs 5/7 - Lecture 25, SCEQs

Tues 5/12 - Exam #4



- we will try to get all your scores up


(exams, Discussion, clickers, HW) so you can choose


if you want to take the nal


Tues 5/19 - Final Exam (cumula9ve) 1 3 pm here


- exam period is over Weds 5/21


- I will automa9cally drop the lowest score of your 5 exams

Two types of gene therapy in humans

Somatic cell gene therapy - introducing a human gene into
somatic human cells to help treat a patient with a disease
- legal, has been accomplished but is still experimental
- has had major setbacks

Germ line gene therapy - introducing a human gene into the

germline of a patient (sperm/eggs) with a genetic disease to
cure the disease in the offspring
- not legal in humans, has been done with mice
- modifications to the human species genome
- proceed with caution
2

5/4/15

Lectures 23 and 24



The Human Genome
Human Gene1c Varia1on

5/4/15

Whole Genome Sequencing

- determining the sequence of an organisms entire genome
Landmarks in genetics and genomics

Gregor Mendel
discovers
laws of genetics

1865

1990

1991

The Human Genome Project

(HGP) launched in
the United States

First US genome
centres established

20

30

30

50

20

75

100

25

125

1900

1905

1992
Genetic Map

cM

Cytogenetic Map

25

Rediscovery of
Mendels work

Archibald Garrod
formulates
the concept
of human
inborn errors
of metabolism

Physical Map
150 Mb

Second-generation
human genetic map developed

Alfred Henry
Sturtevant
makes
the first linear
map of genes

1913

Oswald Avery, Colin MacLeod

and Maclyn McCarty
demonstrate that DNA
is the
hereditary material

1993

U
U

1944

James Watson and

Francis Crick
describe the
double-helical
structure of DNA

1953

Phe
Leu Ser

Tyr

Cys

stop
stop

stop

Trp

Leu Pro

His
Gln

Arg

lle
Met

Thr

Asn

Ser
Arg

Val

Ala

Lys
Asp
Glu

Gly

U
C
A
G
U
C
A
G
U
C
A
G
U
C
A
G

Marshall Nirenberg,
Har Gobind Khorana and
Robert Holley determine
the genetic code

1966

Clone-Based
STS Map

3'

5'

New strands

Stanley Cohen and

Herbert Boyer
develop
recombinant
DNA technology

Frederick Sanger,
Allan Maxam
and Walter Gilbert
develop DNA-sequencing
methods

The Belmont Report

on the use of
human subjects
in research is issued

1972

1974

1994

1995

1996

The HGPs human genetic

mapping goal achieved

The HGPs human physical

mapping goal achieved

First human gene map established

Pilot projects for
human genome
sequencing begin
in the United States

New five-year plan

for the HGP in the
United States published

GenBank
database
established

1977

1982

1997
The DOE forms the
Joint Genome Institute

First human disease gene for

Huntingtons disease is mapped
with DNA markers

1983

First public
discussion
of sequencing
the human
genome

1984

First automated
The polymerase
DNA-sequencing instrument
chain reaction (PCR) is invented
developed

1985

Rapid-data-release
guidelines established
by the NIH and DOE

First gene for

breast cancer
(BRCA1) mapped

1988

1989

1990

2000

2001

2002

2003

Draft version of
human genome
sequence completed

Draft version of human

genome sequence published

Draft version of mouse genome

sequence completed and published

Finished
version of
human
genome
sequence
completed

US President Bill Clinton and

UK Prime Minister Tony Blair
support free access to
genome information

Fruitfly (Drosophila melanogaster)

genome sequenced

Escherichia coli
genome sequenced

Genoscope (French
National Genome
Sequencing Center) founded
near Paris

2003

1999

RIKEN Genomic Sciences

Center established in Japan

Draft version of rice genome

sequence completed and published

Sequence of first human

chromosome
(chromosome 22)
completed

US Equal Employment
Opportunity Commission
issues policy
on genetic discrimination
in the workplace
The HGPs mouse genetic
mapping goal achieved

Human Genome
Organization (HUGO) formed

Full-scale human genome

sequencing begins

Roundworm (Caenorhabditis elegans)

genome sequenced
The Sanger Centre founded
near Cambridge, UK,
(later renamed the Wellcome
Trust Sanger Institute)

1987

Cystic-fibrosis
gene identified by
positional cloning

1998
New five-year plan for the
HGP in the United States published

Yeast (Saccharomyces cerevisiae)

genome sequenced

1986

Sequence-tagged
sites (STS) mapping
concept established

Incorporation of 30,000
genes into human genome map

US National Center
for Human Genome Research becomes
the National Human Genome Research
Institute (NHGRI)

First bacterial genome

(Haemophilus influenzae) sequenced

First-generation
human genetic
map developed

Human
Genome
Project

STS Markers

Development
of yeast artificial
chromosome (YAC)
cloning

Muscular-dystrophy
gene identified
by positional cloning

Desired
fragment
strands

First archaeal
genome sequenced

Sequence Map

Ethical, legal and social

implications (ELSI) programmes
founded at the US National
Institutes of Health (NIH)
and Department of Energy (DOE)

US National Research
Council issues report on
Mapping and Sequencing the
Human Genome

International Nucleotide
Sequence Database
Consortium formed
5'

GATCTGCTA
TACTACCGC
ATTATTCCG
RH Map

Mustard cress
(Arabidopsis thaliana)
genome sequenced

The HGP ends with

all goals achieved

10,000 full-length
human cDNAs sequenced

Mammalian
Gene
Collection

Draft version of
rat genome sequence completed

To be
continued...

Single-nucleotide polymorphism
(SNP) initiative begins

GTGCT
GTCCT
Bermuda principles for
rapid and open data release established

Chinese National Human Genome Centers

established in Beijing and Shanghai

Executive order bans genetic

discrimination in US federal workplace

DESIGN BY DARRYL LEJA

PEAS COURTESY J. BLAMIRE, CITY UNIV. NEW YORK; WATSON & CRICK COURTESY A. BARRINGTON BROWN/SPL; SCIENCE COVERS COURTESY AAAS

2003 Nature Publishing Group

bacteria
(1995)
yeast
(1996)

Human
Genome
Project
launched
(1990)

nematode
(1998)

fruit fly
(2000)

human
(2003)

sequencing the human genome

- in 2003, the human genome sequence was released

- it was a race between a publicly-funded, interna9onal team based in DC
and a private company in Bethesda each chose slightly dierent methods to
determine the sequence of all 3 billion bases in the human genome
- it relied on years of data from working with model organisms
- the two teams 9ed, and reached the nish line at the same 9me
- how was this done?

Celera and Craig Venter
vs.
the public Human Genome Project
The Genome War by James Shreeve (2004)

5/4/15

whole genome shotgun sequencing

5/4/15

Cloning DNA fragments into a plasmid

making a library of human genomic DNA

- digest the en9re human genome
(3 x 109 bp) into random small DNA
fragments (about 2000 bp each)
- clone millions of human genome
fragments into bacterial plasmids and
transform each of them into bacteria

- this is a human genome library
- each plasmid in the library contains
one small piece of the human genome
- we dont know their DNA sequence
- we dont know how the pieces went
together originally!
10

5/4/15

dideoxy or Sanger DNA sequencing

- Fred Sanger (Bri9sh) is only one of two people to win the
Nobel Prize twice in the same eld and one of only four
people to win two Nobel prizes

- Nobel Prize in Chemistry in 1958 for determining the
sequence of human insulin and showing proteins have
dened sequences and structures

- Nobel prize in Chemistry in 1980 with Walter Gilbert for
determining methods to sequence DNA

11

dideoxy or Sanger DNA sequencing

- lacks the 3 OH needed

to add the next nucleo9de

12

5/4/15

dideoxy or Sanger DNA sequencing

13

dideoxy or Sanger DNA sequencing

14

5/4/15

dideoxy or Sanger DNA sequencing

- for sequencing by machine, we use
uorescently tagged dideoxy versions
of the four bases (all in one tube)
- ddATP, ddCTP, ddGTP, ddTTP
- each polymerase stops at a random
place along the chain it is making,
leaving a uorescent tag on the last
base it added
G

NED

G
G

NED

G
G
T

G
G
T
A

ROX

HEX

G
G
T
A
C
6FAM

G
G
T
A
C
G
NED

G
G
T
A
C
G
T

ROX

G
G
T
A
C
G
T
T

G
G
T
A
C
G
T
T
A

ROX

HEX

15

dideoxy or Sanger DNA sequencing

- we can run these DNA fragments

through a capillary tube and they are
separated them by size (smallest rst)
- we use a laser to iden9fy the color of
the tag on each fragment as it comes out
the bodom

16

5/4/15

dideoxy or Sanger DNA sequencing

- we can run these DNA fragments

through a capillary tube and they are
separated them by size (smallest rst)
- we use a laser to iden9fy the color of
the tag on each fragment as it comes out
the bodom
- reading this data on tag colors gives us
the sequence of the DNA strand that
was made

17

5/4/15

assembling the genome sequence

- the sequence of the ends of all the
small fragments is fed into a computer
and a computer algorithm determine
which pieces overlap, and then
assembles them into larger and larger
virtual overlapping fragments called
con9gs
- any gaps between con9gs are lled in
manually
- the resul9ng assembled sequence is
the whole genome sequence of the
organism

19
19

shotgun sequence vs clone by clone sequencing

Craig Venter

Francis Collins

10

5/4/15

Animation

Whole-Genome Shotgun

21

What did we learn from the human genome sequence?

- almost half of our DNA is relics of ancient transposable

elements and viruses, and may not do much

11

5/4/15

What did we learn from the human genome sequence?

What did we learn from the human genome sequence?

- how did they identify all the genes?

- computer algorithms were trained to identify start codons, stop codons,
open reading frames and sites for RNA splicing and to predict genes

12

5/4/15

GENBANK site at NCBI holds all the DNA sequence data

GENBANK site at NCBI holds all the DNA sequence data

Gene9c Sequence Data Bank Feb 2014

157,943,793,171 bases from 171,123,749 reported sequences

13

5/4/15

BLAST site at NCBI Basic Local Alignment Search Tool

- searches your DNA sequence of interest against all known sequences

BLAST site at NCBI Basic Local Alignment Search Tool

- searches your DNA sequence of interest against all known sequences

- builds on what is already known to identify your gene and what it might encode

14

5/4/15

What did we learn from the human genome sequence?

broad categories of of human proteins

- largest categories - most genes encode proteins of unknown func9on

What did we learn from the human genome sequence?

- we can now compare the human genome to the genomes of other species that have
been sequenced, and ask what makes us the same or dierent from other species


Percentage of DNA in human in common with:

Neanderthal
99%

last common ancestor 400,000 years ago
chimpanzee
96%

last common ancestor 7-13 million years ago
cat


90%
cow


80%
mouse

75%

last common ancestor 75 million years ago

fruit y

60%

last common ancestor 600 million years ago
nematode worm 50%

banana

50%

last common ancestor 1.5 billion years ago

15

5/4/15

the human genome, now

- it took 13 years to sequence the first human genome (2003) using
methods developed in the late 1970s, and cost $3 billion
- what have we been doing since then?
1) there has been a worldwide effort to determine more human DNA
sequences, and from different ethnic groups, and to find out how
much genetic diversity, and what kind, exists in the human population
- 2007 - the personal genomes of Jim Watson and Craig Venter were
sequenced
- 2008 - genomes of anonymous Han Chinese and Nigerian were
sequenced
- the Thousand Genome project
- the HapMap project (haplotype mapping)

31

the human genome, now

- it took 13 years to sequence the first human genome (2003) using
methods developed in the late 1970s, and cost $3 billion
- what have we been doing since then?
2) there has been a worldwide effort to determine which human
genetic variants are associated with human diseases, conditions, and
phenotypes
- GWAS genome-wide association studies

32

16

5/4/15

human gene9c varia9on

1) how can we determine if a given person (or animal, or plant or

any kind of cell) carries a particular DNA polymorphism?

2) what can we do with information about the genetic variation in

a specific individual?
3) what can we learn with information about the genetic variation
in our species?

33

Techniques for iden9fying DNA polymorphisms

1) how can we determine if a given person (or animal, or plant or

any kind of cell) carries a particular polymorphism in their DNA?
a) restriction enzyme digestion of the genomic DNA
b) polymerase chain reaction (PCR) analysis of the genomic DNA
c) direct DNA sequencing of the persons genomic DNA
d) SNP analysis on the genomic DNA with microarrays

34

17

5/4/15

35

Restriction Fragment Length Polymorphism - RFLP

36

18

5/4/15

SNP identification by RFLP analysis

37

an RFLP in the beta-globin gene in sickle cell anemia

DdeI site
CTNAG
GANTC

38

19

5/4/15

sickle cell anemia carrier determination by RFLP analysis

can identify carriers for

sickle cell disease

39

Chapter 10 Animation

Testable Genetic Mutations

40

20

5/4/15

Iden9fying DNA polymorphisms

1) how can we determine if a given person (or animal, or plant or

any kind of cell) carries a particular polymorphism in their DNA?
a) restriction enzyme digestion of the genomic DNA
b) polymerase chain reaction (PCR) analysis of the genomic DNA
c) direct DNA sequencing of the persons genomic DNA
d) SNP analysis on the genomic DNA with microarrays

41

simple tandem repeats - STRs

- an STR is a site where a small number of base pairs is repeated

- STRs are abundant in the human genome (one every 2 kb)

- they are very polymorphic (many alleles in the popula9on)

42

21

5/4/15

Polymerase Chain Reaction (PCR)

Each PCR cycle
has 3 steps


a. Mel9ng of DNA (95)


b. Primer hybridiza9on
(~50-60)


c. DNA synthesis (72)

43

Polymerase Chain Reaction (PCR)

- a DNA sequence in the genome can be
greatly amplied by using PCR

- mul9ple rounds of DNA synthesis using
two primers that hybridize to the ends of
the target DNA.

- in each cycle, the amount of target DNA
is doubled.

- aner 30 cycles, there is a billion-fold
increase (230) in the amount of the target
DNA.

- Kary Mullis invented PCR in 1983, and
won the Nobel Prize in 1993

44

22

5/4/15

Simple Tandem Repeat Polymorphism (STRPs)

10 alleles in the popula9on

45

individuals are often heterozygous at an STR locus

can distinguish between two

homozygotes and heterozygote
46

23

5/4/15

- current SNP chips can analyze >500,000 SNPs at once

47

- a persons genomic DNA is

randomly broken up into small
fragments, and all of the fragments
are labeled at one end with a
fluorescent molecule
- the labeled genomic fragment are
then hybridized with the SNPchip
48

24

5/4/15

49
49

50

25

5/4/15

- a laser is shined on the chip and

the fluorescent pattern is recorded
and analyzed by a computer to
find which SNP variants are
present in the persons DNA

51

human gene9c varia9on

- what can we do with this kind of personal gene9c informa9on
1) mapping human disease genes
2) determining a persons suscep9bility to disease based on their genes
3) forensics
4) understanding human evolu9on
5) understanding migra9on and ancestry

52

26

5/4/15

Identifying disease genes using affected families

cys$c brosis

53

Disease genes can be mapped using DNA markers

GWAS - genome-wide association studies

54

27

5/4/15

recent genome-wide association studies (in last 5 years)

- have identified SNPs associated with the many diseases or
conditions:
heart disease
breast cancer
restless leg syndrome (!)`
atrial fibrillation
glaucoma
colon cancer
amyotrophic lateral sclerosis
type 2 diabetes
multiple sclerosis
rheumatoid arthritis
bipolar disorder
slow onset of AIDS

18 SNPs correlated with type 2 diabetes

55

Direct To Consumer gene9c tes9ng services

deCODE
Navigenics
23andme

decodeme.com
navigenics.com
23andme.com

For $600 - $2500 and a sample of saliva, they will report back to
you your SNP pattern for 500,000 SNPs (out of maybe 4 million)
23andme reports on SNPs for 150 traits/conditions/diseases
(for 54 of them, they) give you information about conditions and traits for which there
are genetic associations supported by multiple, large, peer-reviewed studies. Those
associations must also have a substantial influence on a person's chances of developing
the disease or having the trait. Because these associations are widely regarded as
reliable, we use them to develop quantitative estimates and definitive explanations of what
they mean for you.
56

28

5/4/15

Age-related Macular Degenera1on
Alcohol Flush Reac1on
Alpha-1 An1trypsin Deciency
BRCA Cancer Muta1ons (Selected)
BiOer Taste Percep1on
Bloom's Syndrome
Celiac Disease
Crohn's Disease
Cys1c Fibrosis (Delta F508 muta1on)
Earwax Type
Eye Color
G6PD Deciency
Glycogen Storage Disease Type 1a
Hemochromatosis
Lactose Intolerance
Malaria Resistance (Duy An1gen)
Muscle Performance
Non-ABO Blood Groups
Norovirus Resistance
Parkinson's Disease
Prostate Cancer
Psoriasis
Resistance to HIV/AIDS
Rheumatoid Arthri1s
Sickle Cell Anemia & Malaria Resistance
Type 1 Diabetes
Type 2 Diabetes
Venous Thromboembolism

Abdominal Aor1c Aneurysm
Alcohol Dependence
Ankylosing Spondyli1s
An1depressant Response
Asthma
Atrial Fibrilla1on
AOen1on-Decit Hyperac1vity Disorder
Avoidance of Errors
Back Pain
Baldness
Beta-Blocker Response
Bipolar Disorder
Birth Weight
Bladder Cancer
Blood Glucose
Brain Aneurysm
Breast Cancer
Breast Cancer Risk Modiers
Breas`eeding and IQ
C-reac1ve Protein Level
Caeine Metabolism
Celiac Disease: Preliminary Research
Chronic Lymphocy1c Leukemia
Clec Lip and Clec Palate
Cluster Headaches
Colorectal Cancer
Creutzfeldt-Jakob Disease
Developmental Dyslexia
Endometriosis
Esophageal Cancer
Eye Color
Food Preference
Freckling
Gallstones

Gesta1onal Diabetes
Glaucoma
Gout
HDL Cholesterol Level
HIV Progression
Hair Color
Hair Thickness
Heart AOack
Height
Heroin Addic1on
High Blood Pressure (Hypertension)
Intrahepa1c Cholestasis of Pregnancy
Kidney Disease
Larynx Cancer
Longevity
Lou Gehrig's Disease (ALS)
Lung Cancer
Lupus (Systemic Lupus Erythematosus)
Male Infer1lity
Measures of Intelligence
Memory
Mul1ple Sclerosis
Neuroblastoma
Nico1ne Dependence
Obesity
Obesity: Preliminary Research
Obsessive-Compulsive Disorder
Odor Detec1on
Oral and Throat Cancer
Osteoarthri1s
Pain Sensi1vity
Parkinson's Disease: Preliminary Research
Peripheral Arterial Disease
Persistent Fetal Hemoglobin
Placental Abrup1on
57
Preeclampsia

My Beau9ful Genome

Lone Frank 2011

29

5/4/15

Pharmacogenomics

- iden9fying SNPs that correlate with beder or worse responses to certain

drugs will allow beder prescribing by physicians
- example

- codeine is converted to morphine in the liver by the enzyme

cytochrome P450 CYP2D6
- 10% of people have a muta9on that abolishes enzyme func9on
- codeine is of no benet to these people

60

30

5/4/15

Human gene9c varia9on: forensics

- the FBI uses a set of 13 STRs to genotype individuals and
crime scene samples
- they know the number and frequency of the alleles at these
13 sites in Caucasian, African-American, Hispanic and Asian
populations in the US
- obtain crime scene sample
- semen, blood, hair cell, skin cells
- do PCR on each of the 13 loci from the sample and suspects

61

- at one of the real sites used, people have between 5 and 16 repeats of GATA
- so 12 alleles and 78 genotypes (homozygous and heterozygous)

62

31

5/4/15

Human gene9c varia9on: forensics

example - imagine a person matches a semen sample at 13/13 loci, - what is
the chance that he is innocent and this is random bad luck?
- how often would that pattern arise by chance?
- if 13 alleles are present at 50% frequency in population
= 0.5013= 1/8,192

- if 13 alleles are present at 10% frequency in population

= 0.1013 = 1/10,000,000,000,000 (1 in 1013)

64

32

5/4/15

Human gene9c varia9on: forensics

SSR
Crime
sample
Suspect A
Suspect B

3S1358



15, 17



17, 17


15, 17

WA



15, 16



18, 19


15, 16

FGA



23, 27



21, 23


23, 27

3S1358



15, 17



17, 17


15, 17

D21S11



28, 30



27, 30.2


28, 30

D18S51



12, 18



14, 18


12, 18

D5S818



13, 13



9, 12


13, 13

D13S317 D7S820





12, 12 10, 11





12, 12 9, 10




12, 12 10, 11

CSF1PO



8, 11



11, 12


8, 11

TPOX
THO1





7, 8
9.3, 9.3





8, 8
6, 9.3




7, 8
9.3, 9.3

D16S539



9, 13



11, 12


9, 13

Frequency
of Suspect 0.13 0.22 0.31 0.34 0.06 0.11 0.29 0.21 0.26 0.18 0.30 0.38 0.10
Bs genotype

65

Human gene9c varia9on: forensics

- CODIS - FBIs database - Combined DNA Index System
- as of February 2007 it had data from 67,000 crime scenes and 1.5 million
individuals convicted of felonies or arrested for felonies (more recently)
- CODIS has made more than 45,000 hits
- first case and Snowball case

Abraham Lincolns DNA by Philip Reilly (2000)

The Strongest Boy in the World by Philip Reilly (2006)
Tears of the Cheetah by Stephen OBrien (2003)
When a Gene Makes YouSmell Like a Fish by Lisa Seachrist Chiu (2006)
66

33

5/4/15

Human gene9c varia9on: paternity

- similar types of analyses are used in paternity cases
- analysis for one SSR shown
- A = accused males DNA
- C = childs DNA
- M = mothers DNA
- A=C = mixture of A and C

A A C M
+
C

case 1

A A C M
+
C

case 2
67

Human gene9c varia9on: forensics

- can also do this to identify body remains
- 911 victims
- Russian Romanov family (last czar)
- in this case, you use DNA from relatives as the match

68

34

5/4/15

Human gene9c varia9on: human evolu9on

- following human evolution, migration and history via:
- changes in mitochondrial DNA sequence
- changes in human Y chromosome sequence

69

human evolu9on and mitochondrial DNA

- mitochondria (and chloroplasts) are self-replica9ng organelles that
contain their own DNA - supercoiled circles of DNA
- mammalian mtDNA is only 16,500 bp (16.5 kb)
- about 40 genes encode proteins used in mitochondria, such as the
DNA polymerase for replica9ng mtDNA and a few proteins used in
respira9on

70

35

5/4/15

71

human evolu9on and mitochondrial DNA

- human eggs and sperm both contain mitochondria
- aner fer9liza9on, when the sperm and egg fuse, the mitochondria
from the sperm are destroyed, so that all the mitochondria in the
ospring are inherited from the mother
- so genes in the mitochondrial DNA show non-Mendelian inheritance
paderns - uniparental inheritance

- also called extranuclear inheritance or cytoplasmic inheritance

72

36

5/4/15

human evolu9on and mitochondrial DNA

- so human mitochondrial DNA
- is passed only through the maternal side
- does not undergo recombina9on

- therefore, in the absence of new muta9ons, your mitochondrial DNA
is exactly the same as your mothers, grandmothers, etc
- if you went back six genera9ons in your own family tree, you'd see
that your nuclear DNA is inherited from 32 men and 32 women
- your mtDNA, on the other hand, would have come from only one of
those 32 women, on your mothers side.

73

human evolu9on and mitochondrial DNA

- so human mitochondrial DNA
- is passed only through the maternal side
- does not undergo recombina9on

- therefore, in the absence of new muta9ons, your mitochondrial DNA
is exactly the same as your mothers, grandmothers, etc
- if you went back six genera9ons in your own family tree, you'd see
that your nuclear DNA is inherited from 32 men and 32 women
- your mtDNA, on the other hand, would have come from only one of
those 32 women, on your mothers side

- but there is muta9on in mtDNA, from errors during DNA replica9on
and from environmental causes

74

37

5/4/15

human evolu9on and mitochondrial DNA

- star9ng with all the dierent types of mitochondrial DNA variants
present around the world today, we can work backwards to nd a most
recent common ancestor (MRCA)
- the mtDNA molecule that was mutated to give rise
to all exis9ng mtDNA molecules around today


- by applying a molecular clock (1 change/3800 years) we can es9mate
how long ago she lived
- the last female common ancestor of all people currently on the planet
- named Mitochondrial Eve

75

human evolu9on and mitochondrial DNA

1987 - results from analysis of human mtDNA varia9on showed:
- there is twice as much mitochondrial diversity in Africa as in all the rest
of the world
(true for nuclear genes too - there is more diversity in Africa than all the
rest of the world combined)
- 3 of 4 major mitochondrial lineages are found only in Africa,
- 1 mitochondrial lineage is found outside of Africa and it shares a most
recent common ancestor with African lineages about 50,000 YA

76

38

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Figure 17.31: Phylogenetic tree of human mitochondrial DNA

77

human evolu9on and mitochondrial DNA

1987 - results from analysis of human mtDNA varia9on showed:
- there is twice as much mitochondrial diversity in Africa as in all the rest
of the world, and 3 of 4 major mitochondrial lineages are found only in
Africa
- a subset of mitochondrial muta9ons are found outside of Africa - these
share a MRCA with African lineages about 50,000 YA

- believed to be when a small popula9on of humans (5,000?) migrated
out of Africa to populate the rest of the world about 50 - 100,000 YA
- supports the Out of Africa hypothesis put forward by paleontologists
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Figure 17.32: The dispersal of modern human populations

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human evolu9on and

mitochondrial DNA
That's Ridiculous How Could a Single
Being Populate a Planet?

And this is where the confusion sets in. A single
organism can't populate a planet. The evidence didn't
suggest a single woman living in isola1on from
members of her own species. What it suggested was a
gene1c boOleneck a period in human history when
the popula1on was so small that the gene1c
expressions of a single woman could have an impact on
all humans living on the planet today.

She didn't live alone she would have lived within a
community. She didn't just pump babies out, either.
There is no reason to suppose that she had more than
one female child. But there is reason to suppose that
whatever female children she had, they contained
specic advantages for survival over the rest of the
popula1on.

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human evolu9on and the Y chromosome

- the human Y chromosome contains the sex-determining gene SRY which encodes Testis-Determing Factor - tells the developing gonad to
develop as a testis
- the Y chromosome only contains small regions at either end that are
homologous to the X chromosome (called the pseudoautosomal
regions)
- other than this, the Y chromosome has very few genes
- most of the X and Y are not homologous and do not pair during meiosis
- it is assumed that the X and Y chromosomes were once a normal pair of
homologous chromosomes, and that over time the Y has lost sequences
present on the X chromosome

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human evolu9on and the Y chromosome

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human evolu9on and the Y chromosome

- so the Y chromosome is present only in males, and does not go
through recombination along most of its length
- therefore mutations that arise in one male will be passed on to that
males sons without changing
- there are ~30 simple sequence repeats (SSRs) along the Y chromosome
that can be easily mapped
- as was done for females and mtDNA, using the variation in all of the Y
chromosomes in the current human population, it was estimated that the
last common ancestor of all human males lived 50,000 years ago

83

Mapping human history with the Y chromosome

- Genghis Khan - founder of the Mongol Empire in the 13th century
- stretched from China to Europe
- he and his descendants were very prolific
- his son had 40 sons, his grandson Kubilai Khan had 22
- mapping 32 Y chromosome markers from >2000 Asian men showed a
common pattern
- the most recent common ancestor of all the men with this pattern
lived ~1000 years ago - assumed to be Genghis Khan

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Mapping human history with the Y chromosome

- the Lemba are a Bantu-speaking tribe living in S. Africa and Zimbabwe
- they practice male circumcision, have dietary restrictions similar to
those of Jewish people, and have an oral history that says their
ancestors arrived by boat from N. Africa/Middle East
- mapping 12 Y chromosome markers in 136 Lemba men showed they
have two common patterns of variation
- one is similar to the Bantu pattern
- the other is similar to the Cohanim pattern of Jewish people
- the last common ancestor of these men lived 3,000-5,000 years ago,
around the time that the Jews were exiled from Assyria

85

Mapping human history with the Y chromosome

- Gypsies - tribe of nomadic people arriving in Europe about 1000 years
ago - widely persecuted
- called Gypsy because of legend they came from Egypt, but they call
themselves Roma
- their language is similar to languages spoken on the Indian
subcontinent
- 12 million Roma today, in many countries
- Y chromosome analysis of men from 14 Roma populations around the
world showed 45% of them had a related pattern of variation
- the most closely related haplotype is found on the Indian subcontinent,
suggesting this as their site of origin

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gene9cs and human history and migra9on

- dierent groups of people, geographically isolated on the planet, have
dierent paderns of DNA changes (haplotypes) for their genomic DNA
(SNPs), Y chromosomes and mitochondrial DNA
- therefore, you can tell what part of the planet a persons ancestors
came from by examining their DNA and comparing it to samples from
living popula9ons on the planet
- gene9c ancestry tes9ng - $100 - $900
- s9ll allowed 2014

deCODE
Navigenics
23andme

decodeme.com
navigenics.com
23andme.com
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