2007 Melvin Tooker Animal Improvement Programs Laboratory USDA Agricultural Research Service, Beltsville, MD, USA [email protected] [email protected]

2007

Melvin Tooker Melvin Tooker Animal Improvement Programs Laboratory USDA Agricultural Research Service, Beltsville, MD, USA [email protected]

2009

An Introduction to An Introduction to GenomicsGenomics

India Emerging Markets Conference, May 2009 (2) Melvin Tooker200

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Genomic GoalsGenomic Goals

Predict young bulls and cows more accurately

Compare actual DNA inherited Use exact relationship matrix G

instead of expected values in A Trace chromosome segments Locate genes with large effects


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Short historyShort history Illumina BovineSNP50™ BeadChip developed

Accuracy of genomic information assessed by using 2004 evaluations of bulls born before 2000 to predict 2009 evaluations of young bulls

Unofficial genomic evaluations of bull calves provided to industry beginning in April 2008

Jersey results released in October 2008

Over 23,000 animals genotyped through Mar. 2009


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Source of genomic evaluationsSource of genomic evaluations DNA extracted from blood, hair, or semen

~40,000 genetic markers (SNPs) evaluated

For each SNP, difference in PTA estimated between animals with 1 allele compared to the other allele

Genomic data contribute ~11 daughter equivalents to reliability


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How Related are Relatives?How Related are Relatives?

Example: Full sibs • are expected to share 50% of their

DNA on average • may actually share 45% or 55% of

their DNA because each inherits a different mixture of chromosome segments from the two parents.

Combine genotype and pedigree data to determine exact fractions


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Genomic RelationshipsGenomic Relationships

Measures of genetic similarity• A = Expected % genes identical by

descent from pedigree (Wright, 1922)• G = Actual % of DNA shared (using

genotype data)• T = % genes shared that affect a

given trait (using genotype and phenotype)


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Markers vs QTLsMarkers vs QTLs

Models contain markers, not QTLs• M is markers inherited minus freq• M M’ / ∑ p(1-p) = G

List all QTL affecting a trait• Q is alleles inherited minus freq• q contains effects of alleles• u = Q q , var(q) = Vq

• var(u) = E(u u’) = Q Vq Q’ = T


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QTL Relationship Matrix (QTL Relationship Matrix (TT) )

Three bulls have +50 PTA protein. Do they have the same genes?

• Extremely unlikely.• Bull A could have 10 positive genes.• Bull B could have 10 positive genes,

but on different chromosomes.• Bull C could have 20 positive and 10

negative genes.


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Genes in Common at One LocusGenes in Common at One Locus

If Full Sib 1 inherits:

If Full Sib 2 inherits:

w,y w,z x,y x,z

w,y 2 1 1 0

w,z 1 2 0 1

x,y 1 0 2 1

x,z 0 1 1 2

w = gene from sire of sirex = gene from dam of sirey = gene from sire of damz = gene from dam of dam


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Unrelated Individuals?Unrelated Individuals?

No known common ancestors Many unknown common ancestors

born before the known pedigree Relationships in base

• 0 ± x.x% due to earlier ancestors• Called linkage disequilibrium (LD)• Poor terminology, genes may not be

physically linked


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Traditional PedigreeTraditional Pedigree

Sire of Sire

Sire

Dam of Sire

Animal

Sire of Dam

Dam

Dam of Dam


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Genomic PedigreeGenomic Pedigree


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Example of a SNP haplotypeExample of a SNP haplotype

caacgtat

caacggat

SNP

atccgaat

atccgcat

…

… …

…

SNP

tctaggat

tctcggat

SNP

…

…Chr1

Chr2

Haplotype is a set of single nucleotide polymorphisms (SNPs) associated on a single chromosome. Identification of a few alleles of a haplotype block can identify other polymorphic sites in the region.

Haplotype 1 tca

gac Haplotype 2


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SNP PedigreeSNP Pedigreeatagatcgatcg

ctgtagcttagg

agggcgcgcagt

cgatctagatcg

cggtagatcagt

agagatcgatct

atggcgcgaacg

ctatcgctcagg

ctgtagcgatcg

agatctagatcg

agagatcgcagt

atgtcgctcacg

ctgtctagatcg

atgtcgcgcagt


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Haplotype PedigreeHaplotype Pedigreeatagatcgatcg

ctgtagcttagg

agggcgcgcagt

cgatctagatcg

cggtagatcagt

agagatcgatct

atggcgcgaacg

ctatcgctcagg

ctgtagcgatcg

agatctagatcg

agagatcgcagt

atgtcgctcacg

ctgtctagatcg

atgtcgcgcagt


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Translate Haplotype to GenotypeTranslate Haplotype to Genotype

agatctagatcg

111211120200

ctgtagcgatcg


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Genotype PedigreeGenotype PedigreeCount number of second alleleCount number of second allele

121101011110

111211120200

101121101111

122221121111

101101111102

011111012011

121120011010

0 = homozygous for first allele (alphabetically)1 = heterozygous2 = homozygous for second allele (alphabetically)


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Genotype Data for ElevationGenotype Data for Elevation Chromosome 1Chromosome 1

10001112200200121110111121111011110011211000201220022201111202101200211122110021112001111001011011010220011002201101120020110102022212112210201001110001122022122211202112012020100202202000021100011202011221112111022011110000212202000221012020002211220111012100111211102112110020102100022000220100020110000220221102211210112111012222001211212220020002002020201222110022222220022121111210021111200110111011200202220001112011010211121211102022100211201211001111102111211021112200010110111020220022111010201112111101120210210212110110221220012110112110120220110022200210021100011100211021101110002220020221212110002220102002222121221121112002011020200122222211221202121121011001211011020022000200100200011110110012110212121112010101212022101010111110211021122111111212111210110120011111021111011111220121012121101022202021211222120222002121210121210201100111222121101


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Genotype Data from Inbred BullGenotype Data from Inbred BullChromosome 24 of MegastarChromosome 24 of Megastar

102122210102102101110211011211221121100220200022202000202022000002200202222022020000200202222220000202222000002202000020022002000000222200022220000000000020222022002000222020222220002202222222220000200220202220200020002200000000220222000000220020200022220020200200202022202222222202220200020220220222202022202020202200022002220220022200000220200002002002000200222220002222020200222002220200002020000002222202020000200200222200020220222200220002222022002222020200022022022220022200220002002202000002200220222000022000022000222202002222000220020020202202000222000222002220220220000022022002002002022000200022220220022200202202002222022200000202200020200202020002200220000022022200202220200022002000200022002002000200220222220022022000200002000200002022002022020020000222000022200200020022200002202200200220022022020202020202000222020002202002022022202200002020200002020200022222200222200020022022220000020220020200202022022020200002000200220220002200


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Genotype Parents and Grandparents

Manfred

O-Man

Jezebel

O-Style

Teamster

Deva

Dima


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Expected Relationship MatrixExpected Relationship Matrix11

1HO9167 O-Style1HO9167 O-Style

PGS PGD MGS MGD Sire Dam Bull

Manfred 1.0 .0 .0 .0 .5 .0 .25

Jezebel .0 1.0 .0 .0 .5 .0 .25

Teamster .0 .0 1.0 . 0 .0 .5 .25

Dima .0 .0 .0 1.0 .0 .5 .25

O-Man .5 .5 .0 .0 1.0 .0 .5

Deva .0 .0 .5 .5 .0 1.0 .5

O-Style .25 .25 .25 .25 .5 .5 1.0

1Calculated assuming that all grandparents are unrelated


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Pedigree Relationship MatrixPedigree Relationship Matrix1HO9167 O-Style1HO9167 O-Style


Manfred 1.053 .090 .090 .105 .571 .098 .334

Jezebel .090 1.037 .051 .099 .563 .075 .319

Teamster .090 .051 1.035 .120 .071 .578 .324

Dima .105 .099 .120 1.042 .102 .581 .342

O-Man .571 .563 .071 .102 1.045 .086 .566

Deva .098 .075 .578 .581 .086 1.060 .573

O-Style .334 .319 .324 .342 .566 .573 1.043


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Genomic Relationship Matrix Genomic Relationship Matrix 1HO9167 O-Style1HO9167 O-Style


Manfred 1.201 .058 .050 .093 .609 .054 .344

Jezebel .058 1.131 .008 .135 .618 .079 .357

Teamster .050 .008 1.110 .100 .014 .613 .292

Dima .093 .135 .100 1.139 .131 .610 .401

O-Man .609 .618 .014 .131 1.166 .080 .626

Deva .054 .079 .613 .610 .080 1.148 .613

O-Style .344 .357 .292 .401 .626 .613 1.157


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Difference (Genomic – Pedigree) Difference (Genomic – Pedigree) 1HO9167 O-Style1HO9167 O-Style


Manfred .149 -.032 -.040 -.012 .038 -.043 .010

Jezebel -.032 .095 -.043 .036 .055 .004 .038

Teamster -.040 -.043 .075 -.021 -.057 .035 -.032

Dima -.012 .036 -.021 .097 .029 .029 .059

O-Man .038 .055 -.057 .029 .121 -.006 .060

Deva -.043 .004 .035 .029 -.006 .087 .040

O-Style .010 .038 -.032 .059 .060 .040 .114


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ConclusionsConclusions

Relationships can be defined as:• A = expected genes in common• G = actual DNA in common• T = QTL alleles in common for a trait

Full sibs share 50% ± 3.5% of DNA. “Unrelated” animals share more or

fewer unknown ancestors than average. Reliability can increase if genomic (G)

replace traditional (A) relationships


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Where are the Major Genes?Where are the Major Genes?


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Distribution of Marker Effects (Distribution of Marker Effects (Net MeritNet Merit))


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Distribution of Marker Effects (Distribution of Marker Effects (DPRDPR))


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Marker Effects on WebsiteMarker Effects on Website


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Positive or Negative TraitsPositive or Negative Traits


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From whom did the bad allele come?From whom did the bad allele come? Round Oak Rag Apple Elevation (7HO00058)


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Net Merit by ChromosomeNet Merit by ChromosomeFreddie (1HO08784)Freddie (1HO08784) - highest Net Merit bull - highest Net Merit bull


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Net Merit by ChromosomeNet Merit by Chromosome O Man (7HO06417)O Man (7HO06417) – Sire of Freddie – Sire of Freddie


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Net Merit by ChromosomeNet Merit by ChromosomeDie-Hard (29HO08538) Die-Hard (29HO08538) - maternal grandsire- maternal grandsire


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New Chromosomal PTA QueryNew Chromosomal PTA Query


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Chromosomal PTA Query ExampleChromosomal PTA Query Example


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AcknowledgmentsAcknowledgments

Genotyping and DNA extraction:• USDA Bovine Functional Genomics Lab, U.

Missouri, U. Alberta, GeneSeek, Genetics & IVF Institute, Genetic Visions, and Illumina

Computing: • AIPL staff (Mel Tooker, Leigh Walton, Jay

Megonigal) Funding:

• National Research Initiative grants– 2006-35205-16888, 2006-35205-167012006-35205-16888, 2006-35205-16701

• Agriculture Research Service• Holstein, Jersey & Brown Swiss breed associations• Contributors to Cooperative Dairy DNA Repository

(CDDR)

Documents

2007 Melvin Tooker Animal Improvement Programs Laboratory USDA Agricultural Research Service, Beltsville, MD, USA [email protected] [email protected]