Download History of Disease Gene Mapping

Lectures on Human Genetics
I. History of Disease Gene Mapping
II. Statistical Genetics
III. Genes and Environment
28 Nov 2013
Jurg Ott, Ph.D.
Institute of Psychology
Chinese Academy of Sciences, Beijing
Rockefeller University, New York
Laboratory of Statistical Genetics
http://lab.rockefeller.edu/ott/
Aspects of Gene Mapping






Scientific
Statistical, methodological
Computational
Commercial
Interpersonal
Historical
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1
Gregor Mendel, 1822-1884
Monk at monastery in Brünn
 Experiments
p
on g
garden
pea convince him that
phenotypes are determined
by inherited “factors” (now
called genes)
 Formulation of the
“mendelian” laws of
inheritance
 Inheritance is particulate,
not a blending of various
forces
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Mendel’s paper
 Mendel GJ (1866)
Versuche über
Pflanzen-Hybriden.
Verh Naturforsch
Ver Brünn 4:3-47
 Ignored until
rediscovered in
early 1900s
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2
Mendelian Inheritance of disease
Dominant
D/N
N/N
N/N
D/N
Recessive
D/N
D/N
Large family
pedigrees, many
generations
D/D
D/N
D/N
N/N
Tend to occur in
single sibships,
one generation
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Chromosomes and Mendel’s laws
Sutton & Boveri, years 1902-1904
 Theory: Mendel’s
Mendel s genes are located on
the chromosomes
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3
“Fly room,” Columbia University
Thomas H. Morgan, early 1900s
 Experiments with fruitfly,
Drosophila.
 Alfred H. Sturtevant,
undergraduate student,
detected linear arrangement
of genes on the X
chromosome
c
o oso e → ge
genetic
et c
linkage, linkage mapping
 Sturtevant & Lewis (2001) A
History of Genetics
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Heritable Diseases
 Rare Diseases (prevalence < 1%)
 Mendelian inheritance, easy to recognize
 Examples: Color blindness, Huntington disease, cystic
fibrosis. 1 disease gene each.
 Common Diseases
 Non-mendelian (“complex”) mode of inheritance.
Examples: Diabetes, schizophrenia, obesity.
 Genetically relevant phenotype often unclear
 Multiple underlying susceptibility genes
 Traits due to environment
 To be discussed in lecture 3
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4
First assignment of a disease
gene to a chromosome
 E. B. Wilson, 1911. Columbia University, New York
 Subsequently, ~35 disease genes assigned to X chrom.
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Genetic Linkage
Assumed example



Father received AB
chromosome from
grandma and ab from
grandpa. Phase known.
When he makes sperm,
in meiosis, crossovers
occur leading to
recombinant offspring,
but rarely between two
loci close to each other.
Recombination fraction
θ = measure for genetic
distance. Unit: θ = 1%
→ 1 cM (centimorgan)
Direct estimate:
̂ /n, k = number
θ=k
of recombinants in
n meioses
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5
Estimating θ: y statistics
Bernstein (1931) Z Abst Vererb 57:113-138




Grandparents unknown: Number of recombinants and
nonrecombinants depends
p
on p
phase. Can use 2-generation
g
data.
Define k = number of recombinants for a given phase. No direct
estimate of θ possible.
But y = k (n – k)
is the same for
each phase; y = 0
for θ = 0, and is
largest for θ = ½.
Here y = 3.
Here,
3
Fisher (later): y
statistics do not
make use of all
information in
data.
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Penrose’s sibpair method
Penrose (1935) Ann Eugen 6:133-138
 Idea: Given two traits with a genetic basis, siblings
concordant for the trait are genetically similar (share
susceptibility alleles); if so for two traits
traits, these traits are
genetically linked.
 Linkage analysis possible on the basis of a single
generation: sibpairs.
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6
Penrose’s sibpair method
Ott (2011) Ann Hum Genet 75:344 (review on linkage papers in Annals)
 Potential problem: Sibpairs
i larger
in
l
sibships
ib hi are nott
independent.
 Method inefficient, contains
much useless information.
 Nonetheless, became wildly
popular. Large numbers of
linkage studies published,
mostt with
ith negative
ti results.
lt
 Example: Boyd & Boyd (Ann Eugen [1941] 11:1-9) scored
500 sibpairs for such phenotypes as presence of hair in
the mid-digital regions of the fingers, ability to taste
phenyl-thiocarbamide (PTC), and various blood types.
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First autosomal linkage
Mohr (1951) Acta Pathol Microbiol Scand 28:207-210
Penrose (1946) Ann Eugen 13:25-29
Jan Mohr
 U
Using
i
sibpair
ib i data
d
analyzed
l
db
by P
Penrose’s
’
extended method, Jan Mohr (1921-2009)
detected linkage between the Lutheran
blood group (LU) and the Secretor locus
(Se), but chromosomal location as yet
unknown. In 1954, he reported a linkage
of myotonic dystrophy with the above loci.
 Linkage relations between various loci on the X
chromosome had been found earlier by the maximum
likelihood method…
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7
Maximum likelihood estimation
Julia Bell & J.B.S. Haldane (1937) Proc Roy Soc B 123:119
 General statistical method, introduced by R.A. Fisher, for
estimating
ti
ti parameters
t
such
h as θ.
θ Compute
C
t L(θ) = P(data;θ)
P(d t θ)
and vary θ between 0 and ½ until L(θ) is maximized.
 Bell & Haldane:
 Exact calculation of L(θ) for colorblindness versus
hemophilia, considered “unduly cumbrous.”
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Colorblindness vs. hemophilia
Haldane & Smith (1947) Ann Eugen 14:10-31
 H
Here too,
t
exactt
calculation of L(θ) and
L ratio, L(θ)/L(½).
 Easier to work with
lod score, Z(θ) =
log10[L(θ)/L(½)].
 No possibility yet to
do these calculations
for autosomal family
pedigrees.
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8
Autosomal linkage in small families
Newton E. Morton (1955) Am J Hum Genet 7:277-318
 F
Famous publication;
bli ti
1,234
1 234 citations
it ti
 For small family types, developed lod scores at fixed θ
values, published in tables.
 Recommendation: Researchers should publish their own
lod scores at θ = 0.01, 0.05, 0.10, …, 0.40.
 Significance test: Implemented Wald’s sequential
probability ratio test of θ = 0.20 versus θ = 0.50. Rule:
C
Combine
bi lod
l d scores over families
f
ili and…
d



stop and declare linkage if Z(θ) > 3
stop and declare no linkage if Z(θ) < -2
otherwise, continue sampling families
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Newton E. Morton
D.C. Rao (2012) Genet Epidemiol 37:131-135

Morton’s 1955 work was the foundation for the next 20 years of
linkage
g analysis.
y
Worked in Hawaii, New York, University of Southampton.

Stephanie Sherman, Michael Conneally, Newton Morton, James Crow

Morton’s 70th
birthday in 1999
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9
Newton E. Morton
http://www.jurgott.org/linkage/

Morton’s 70th birthday in 1999
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MIM – Mendelian Inheritance of Man
McKusick (1966) Johns Hopkins University Press, Baltimore
Catalog of heritable human diseases
Maintained on computer since 1964
Put online as OMIM in 1987
Highly recommended: McKusick (2006)
“A 60-year tale of spots, maps, and genes”
Annu Rev Genomics Hum Genet 7:1-27
 Contains various stories, for example,
about Renwick’s linkage program, written
in machine code




J. Ott "Gene Mapping History"
Victor A.
McKusick
20
10
First assignment of a gene to an
autosome
Roger Donahue et al (1968) Proc Natl Acad Sci USA 61:949-955

Linkage analysis of Duffy (Fy) blood group locus with the “uncoiler” chromosomal polymorphism on chromosome 1,
1 which segresegre
gated in Donahue’s family as a heritable secondary constriction.
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Maps
 ““Map”” generally
ll
2-dimensional
 Human genetics:
 Linear arrangement of genes
 Different (types of) maps, depending on metric
 Linkage map, unit of centimorgan (cM) = 1%
recombination
bi ti
fraction
f
ti
(at
( t small
ll distance)
di t
)
 Physical map, unit of 1 megabase (MB) = 1 mio
basepairs. Very roughly, 1 MB = 1 cM
 LD map in units of linkage disequilibrium, radiation
hybrid maps,etc.
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11
Human Gene Mapping workshops


HGM1 in New Haven,
Haven 1973
Many more workshops over the years.

Committees
compiled results
and recommended
procedures and
rules for
nomenclature.
Genes to be
mapped: Mostly
blood groups (ABO,
Rh, …) and enzyme
polymorphisms.

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Linkage in general pedigrees
Elston & Stewart (1971) Hum Hered 21:523-542
Robert C. Elston
 Method for calculating
likelihood in large family
pedigrees; 1,166 citations.
 Numerical recursive
calculation, “receipe” rather
than formula. ES algorithm.
 Opened possibilities for linkage
analysis in large pedigrees
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12
The LIPED program
Ott (1974) Am J Hum Genet 26:588-597
Ott (1976) Am J Hum Genet 28:528-529



Implemented the ES algorithm in a FORTRAN IV program for
li k
linkage
analysis;
l i 1
1,263
263 citations.
it ti
For the next 10 years, LIPED was the only generally available
program for linkage analysis in large families. Used worldwide to
genetically map disease genes.
Initially used with 16 enzyme polymorphisms and blood groups.
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Familial Hypercholesterolemia
Ott et al (1974) Am J Hum Genet 26:598-603
 Alaska kindred with many affected




iindividuals.
di id l Cholesterol
Ch l t
l level
l
l > 95th
%ile of normal → affected
LIPED program showed mild evidence
of linkage to C3 polymorphism
Later confirmed by Elston, Berg. This
demonstrated existence of a disease
gene in the vicinity of C3 (chrom. 19)
Work by Joe Goldstein and Michael
Brown (Nobel prize in 1985) identified
disease as defect in LDL receptor;
located on chromosome 19.
Now drugs (statins) have been
developed for lowering cholesterol
level.
J. Ott "Gene Mapping History"
Alaska kindred
with familial
hypercholesterolemia
(Schrott et al
1972)
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13
Genetic markers
 Before 1980
1980, up to 60 blood groups and enzyme




polymorphisms used
Botstein et al (1980): DNA polymorphisms,
RFLPs, 2 alleles each
VNTRs, highly polymorphic, panel of 800
markers used
SNPs, origin in single mutation, very stable,
several million known, 2 alleles each
Ultimate resolution: Basepairs from DNA
sequencing
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Huntington Disease
Gusella et al (1983) Nature 306:234
Bates (2005) Nat Rev Genet 6:766
 Dominant inheritance, average age at onset 35 years.
 Venezuela pedigree (Nancy Wexler)
Wexler), 18,000
18 000 individuals over 10
generations
 Using RFLPs and the LIPED program, Gusella et al (1983)
mapped HD to a location on chromosome 4.
 Duyao et al (1993) Nat Genet 4:387 – HD caused by CAG
repeats. Normal range: up to 35 repeats; HD: 40+ repeats
 Potential legal issues (insurance)
 1983: HD Foundation donated IBM PC to me for multipoint
mapping.
mapping
American HD family
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14
Human Gene Maps
 Lathrop/Lalouel/Julier/Ott (1984) Proc Natl Acad Sci USA
81:3443. Multilocus linkage analysis with LINKAGE programs.
 First map: Helen Donis-Keller et al (1987) Cell 51:319. 403
markers, mostly RFLPs
 Dausset et al (1990) Genomics 6:575. CEPH families for

collaborative mapping
NIH/CEPH Collaborative Mapping Group (1992) Science 258:6786. “A genetic linkage map of the human genome was
g 279 genes
g
and
constructed that consists of 1416 loci,, including
expressed sequences. The loci are represented by 1676
polymorphic systems genotyped with the CEPH reference
pedigree resource. A total of 339 microsatellite repeat markers
assayed by PCR are contained within the map.”
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Breast Cancer
Hall, …, King (1990) Science 250:1684
http://www.google.com/patents/US5837492
 Linkage of early onset disease gene,
gene BRCA1
BRCA1,
to chromosome 17q 21
 Used LIPED and LINKAGE programs
Mary-Claire King
 Mark Skolnick, CEO of Myriad Genetics in Salt Lake City,
Utah, wins race to find BRCA2 on chromosome 18
 17 Nov 1998: Patent for “methods and materials used to
i l
isolate
and
d detect
d
a human
h
breast
b
cancer predisposing
di
i
gene (BRCA2), some mutant alleles of which cause
susceptibility to cancer, in particular breast cancer”
 13 June 2013: U.S. Supreme court strikes down Myriad
Genetics’ patent
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Mapping methods
McKusick (1991) FASEB J 5:12-20
 Linkage analysis


predominant
through 1980
Risch & Merikangas
(1996) Science
273:1516.
Association analysis
more powerful than
linkage analysis for
variants of small
effect on disease;
complex traits.
Case-control studies
GWAS.
Now, sequence data are again obtained preferentially in human
families; re-emergence of linkage analysis
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First genomewide screen with
SNP chips Science 308, 358-389 15 Apr 2005
Josephine
Hoh
Genome-wide
screen, n = 116,204
SNPs, strong
association of a
variant and AMD.
Robert
Klein
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GWAS misguided?
McClellan & King (2010) Cell 141:210

“Strong evidence suggests that rare mutations of severe effect are
responsible for a substantial portion of complex human disease”

“new alleles constantly arise, at an estimated rate of
approximately 175 per diploid human genome per generation”

“common disease-common variant model … genome-wide
association studies (GWAS) have published hundreds of common
variants whose allele frequencies are statistically correlated with
various illnesses and traits. However, the vast majority of such
variants have no established biological relevance to disease or
clinical utility for prognosis or treatment”

“A Time to Sequence— Genome-wide screening for mutations
remains the most effective and unbiased way to discover genes
involved in complex illnesses”
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Sequencing the
Human Genome





J. Craig Venter. 984-92 Researcher at
NIH. S
NIH
Sequenced
d 1000s
1000 off human
h
gene
fragments. NIH filed for patents.
1992: Set up The Institute for Genomic
Research (TIGR).
May 1998: Joined forces with ABI
/Perkin-Elmer to sequence human
genome in three years. Direct
competition with NIH sequencing effort.
“It was the methods, not the machines”
Time magazine 2007 and 2008: Among
the 100 most influential people in the
world.
Autobiography, A life decoded. Shows
how scientists really work…
J. Ott "Gene Mapping History"
Venter et al
(2001) The
sequence of
th human
the
h
genome.
Science 291,
1304-51
34
17
Nat Rev Genet
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Nat Rev Genet
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Acknowledgments
http://lab.rockefeller.edu/ott/associates
 Research grants from NIH and Chinese
government
 My former students and faculty members
 Former students in Beijing now in U.S.:




Zhe Liu, U Chicago
Yuanyuan Shen,
Shen Harvard U,
U Boston
Gao Wang, Rice U, Houston
Xu Shu, U Michigan, Ann Arbor
J. Ott "Gene Mapping History"
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