An Introduction to Genomics

1
An Introduction to Genomics
2
Genomic 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

3
Short 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

4
Source 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

5
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

6
Genomic 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)

7
Markers 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

8
QTL Relationship Matrix (T)

• 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.

9
Genes in Common at One Locus
w gene from sire of sire x gene from dam of
sire y gene from sire of dam z gene from dam
of dam
10
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

11
Traditional Pedigree
12
Genomic Pedigree
13
Example of a SNP haplotype
SNP
SNP
SNP
caacgtat
atccgcat


tctaggat

Chr1
caacggat
atccgaat


tctcggat

Chr2
Haplotype 1
tca
gac
Haplotype 2
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.
14
SNP Pedigree
atagatcgatcg
ctgtagcttagg
ctgtagcgatcg
agatctagatcg
agggcgcgcagt
cgatctagatcg
ctgtctagatcg
cggtagatcagt
atgtcgcgcagt
agagatcgatct
agagatcgcagt
atggcgcgaacg
atgtcgctcacg
ctatcgctcagg
15
Haplotype Pedigree
atagatcgatcg
ctgtagcttagg
ctgtagcgatcg
agatctagatcg
agggcgcgcagt
cgatctagatcg
ctgtctagatcg
cggtagatcagt
atgtcgcgcagt
agagatcgatct
agagatcgcagt
atggcgcgaacg
atgtcgctcacg
ctatcgctcagg
16
Translate Haplotype to Genotype
ctgtagcgatcg
agatctagatcg
111211120200
17
Genotype PedigreeCount number of second allele
0 homozygous for first allele
(alphabetically) 1 heterozygous 2 homozygous
for second allele (alphabetically)
18
Genotype Data for Elevation
Chromosome 1
10001112200200121110111121111011110011211000201220
02220111 12021012002111221100211120011110010110110
10220011002201101 12002011010202221211221020100111
00011220221222112021120120 20100202202000021100011
20201122111211102201111000021220200 02210120200022
11220111012100111211102112110020102100022000 22010
00201100002202211022112101121110122220012112122200
200 0200202020122211002222222002212111121002111120
011011101120 0202220001112011010211121211102022100
211201211001111102111 2110211122000101101110202200
221110102011121111011202102102 1211011022122001211
011211012022011002220021002110001110021 1021101110
002220020221212110002220102002222121221121112002 0
11020200122222211221202121121011001211011020022000
2001002 000111101100121102121211120101012120221010
1011111021102112 211111121211121011012001111102111
1011111220121012121101022 202021211222120222002121
210121210201100111222121101
19
Genotype Data from Inbred BullChromosome 24 of
Megastar
10212221010210210111021101121122112110022020002220
20002020220 00002200202222022020000200202222220000
20222200000220200002002 20020000002222000222200000
00000020222022002000222020222220002 20222222222000
02002202022202000200022000000002202220000002200 20
20002222002020020020202220222222220222020002022022
022220202 2202020202200022002220220022200000220200
002002002000200222220 0022220202002220022202000020
200000022222020200002002002222000 2022022220022000
222202200222202020002202202222002220022000200 2202
00000220022022200002200002200022220200222200022002
0020202 202000222000222002220220220000022022002002
0020220002000222202 200222002022020022220222000002
0220002020020202000220022000002 202220020222020002
2002000200022002002000200220222220022022000 200002
00020000202200202202002000022200002220020002002220
00022 02200200220022022020202020202000222020002202
00202202220220000 20202000020202000222222002222000
20022022220000020220020200202 02202202020000200020
0220220002200
20
Genotype Parents and Grandparents
21
Expected Relationship Matrix11HO9167 O-Style
1Calculated assuming that all grandparents are
unrelated
22
Pedigree Relationship Matrix1HO9167 O-Style
23
Genomic Relationship Matrix 1HO9167 O-Style
24
Difference (Genomic Pedigree) 1HO9167 O-Style
25
Conclusions

• 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

26
Where are the Major Genes?
27
Distribution of Marker Effects (Net Merit)
28
Distribution of Marker Effects (DPR)
29
Marker Effects on Website
30
Marker Effects on Website
31
Marker Effects on Website
32
Positive or Negative Traits
33
From whom did the bad allele come? Round Oak Rag
Apple Elevation (7HO00058)
34
Net Merit by ChromosomeFreddie (1HO08784) -
highest Net Merit bull
35
Net Merit by Chromosome O Man (7HO06417) Sire
of Freddie
36
Net Merit by ChromosomeDie-Hard (29HO08538) -
maternal grandsire
37
New Chromosomal PTA Query
38
Chromosomal PTA Query Example
39
Acknowledgments

• 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, 2006-35205-16701
• Agriculture Research Service
• Holstein, Jersey Brown Swiss breed associations
• Contributors to Cooperative Dairy DNA Repository
  (CDDR)