Finding Genes Controlling Complex

Phenotypes

Elaine Ostrander, PhDNational Human Genome Research Institute

National Institutes of Health

Methodology and Approaches

• Whole Genome Association Studies– Human Height– Obesity– Behavior– Others

• Animal Models– Skin Color– Skeletal Size– Leg length– Racing Speed

WGA Association Studies Associated with Height

• GWA scan data • Multiple SNPs in strong LD with each other reached genome wide levels of significance

• Mice with with homozygous deletions at this locus are short in stature

Frayling et al., (2007). Science April 12

• In whole genome association studies encompassing over 38,000 subjects, common set of variants in FTO gene were found to be associated with increased BMI.

• Result grew out of study of diabetes and represents increased risk for both disease and obesity.

• No mechanistic data. Appears that risk is mediated through changes in fat mass.

• 16% of adults who are homozygous for the risk allele weigh 3 Kg more and had 1.67 fold increased risk of obesity than those without risk allele.

Genetics of Obesity

Implication

s for Society are Enormous

Societal traits perceived to be advantageous or desirable:

tall and thin• Discrimination--obesity predisposes to variety of health problems diabetes, heart disease, blood pressure, etc.

Sports--Preselection and training of individuals Taller: basketball, volleyball Shorter: jockey, ice skater, gymnastics

Thinner: runner, dancer

Genetics of Skin Color

Genetics of Skin Color• golden gene (SLC24A5 in humans) encodes a cation exchanger that localizes to the melanosome or its precursor.

• Protein product affects pigmentation in both zebrafish and humans

• Melanophores of golden mutations are smaller, more pale, more transparent, and contain fewer melanosomes

Lamason et al., (2005) Science 310:1782-1786

wt

wt

gol

gol

Region of decreased heterozygosity in Europeans at SLC24A5 gene•Conservation of

ancestral allele predominates in African and East Asian populations.•Variant allele is nearly fixed in European populations correlating with lighter skin..•Study suggest that SLC24A5 explains 25-38% of the European-African difference in skin melanin index. Lamason et al., (2005) Science 310, 1782 -1786

Mapping Variation in the Canine System

•Each breed fixed for specific traits•Creation of breeds recent and rapid•Small number of genes responsible for many complex traits

Sutter et al., (2007) Science 316:112-5

Strong Statistical Association With Skeletal Size In Portuguese

Water Dogs IGF1

Identical Selective Sweep Across IGF1 in 14 Small Dog Breeds

Achondroplasia Force vs. speed axisof variation

Body size

Mapping Breed-Fixed Morphology

Brachycephaly

Herding behavior

Performance Enhancing Polymorphisms:

Genes Controlling Racing Speed In Dogs

Mosher et al., (2007) PLoS Genetics

(in press)

Belgian Blue Cattle

•“Bully” whippets appear similar to other species with “double muscle” phenotype. •Phenotype caused by two copies of a 2 bp deletion in exon 3 removes the latter 17% of the protein disrupts structure

Bully Whippet

Muscle Mass Controlled in Part by Levels of Myostatin

Dogs Heterozygous for the MSTN Deletion Show an Intermediate Phenotype

P ≈ 7.43 x 10-6 ; Kruskal-Wallis

Test

P = 0.0015; Kruskal-Wallis

test

P = 3.47 x 10-5; Kruskal-Wallis

test

Mh mutation explains 60% of the variation

in measurements

Could this increased musculature affect a

dog’s speed?

MSTN Deletion is Overrepresented in Grade A Racers

Fisher’s Exact Test:A vs B,C,D P=0.00027 AB vs CD P=0.00073A vs B P=0.086C vs D P=0.42Kendall’s NP P ~ 0.000283

MSTN in Athletics• Are similar mutations found in other competitive or high

performing groups?• What other performance-enhancing polymorphisms remain to be

found? Many?• Vital area of research for both humans and animals

• Little is known about risks and side effects

Vogel. Science (2004)Sweeney. Sci. Am. (2004)

Genetics of Behavior• Dozens of putative loci identified for behavioral disorders and many others – Bipolar disorder, Schizophrenia– Autism– ADD and ADHD– Etc.

• Ongoing canine studies for: – “Rage” in English Spring Spaniels– Obsessive Compulsive Disorder in Bull Terriers

– Naturally occurring behaviors such as prey drive, herding, learning, etc.

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Summary The question of Nature versus Nurture

remains, except now we know a great deal more about the “nature” part.

Will this knowledge affect our collective behaviors?• Will we as a society and as

individuals continue to view ourselves as full of potential?

• Or will our genetic profiles make us self-limiting?

Next inroads must be into genetic loci affect our ability to rise above our “genetic mandates”