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Towards a Complete Mouse Haplotype Map. Mathew Pletcher Genomics Institute of the Novartis Research Foundation. SNP Discovery. Selected 2800 loci based on RH map positions Sequenced loci from 8 inbred strains ( A/J, BALBc/ByJ, CAST/Ei, C3H/HeJ, C57BL/6J, DBA/2J, SPRET/Ei, 129SvIm/J )

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slide1

Towards a Complete Mouse

Haplotype Map

Mathew Pletcher

Genomics Institute of the Novartis Research Foundation

slide2

SNP Discovery

  • Selected 2800 loci based on RH map positions
  • Sequenced loci from 8 inbred strains
  • (A/J, BALBc/ByJ, CAST/Ei, C3H/HeJ, C57BL/6J, DBA/2J, SPRET/Ei, 129SvIm/J)
  • Identified approximately 15,500 SNPs – all publicly available at dbSNP and the Jax Phenome Database
  • SNPview – a viewer to display SNP distributions
  • and patterns (http://www.gnf.org/SNP/)
slide3

assembly

chromosome

position

strains

view

SSLPs

SNPview (http://www.gnf.org/SNP/)

slide6

SNP Distribution and Analysis for Chr. 4

SNPs can be viewed as:

SNP alleles

Major and minor alleles

Haplotypes

BALB/cByJ

A/J

DBA/2J

C3H/HeJ

C57BL/6J

129/SvImJ

CAST/Ei

SPRET/Ei

211 loci

BALB/cByJ

A/J

DBA/2J

C3H/HeJ

C57BL/6J

129/SvImJ

BALB/cByJ

A/J

DBA/2J

C3H/HeJ

C57BL/6J

129/SvImJ

0

30.4

60.8

91.2

131.6

162

Pos, Mbp

slide7

400

300

DBA/2J/A/J

SNPs/500 kbp

200

100

0

A/J

DBA/2J

0

0

5

5

10

10

15

15

20

20

25

25

30

30

35

35

40

40

45

45

50

50

55

55

60

60

65

65

70

70

75

75

80

80

85

85

90

90

95

95

700

600

C57BL/6J/A/J

500

SNPs/500 kbp

400

300

200

100

0

A/J

C57BL/6J

Chromosome Length Mbp

SNP Density on Chromosome 16

Celera data

slide8

100

90

80

C57BL/6J/A/J

70

C57BL/6J/DBA/2J

C57BL/6J/129X1/SvJ

A/J/DBA/2J

60

A/J/129X1/SvJ

DBA/2J/129X1/SvJ

50

%bins/<100 SNPs

40

30

20

10

0

Celera data

Chr.1

Chr.4

Chr.6

Chr.5

Chr.7

Chr.2

Chr.3

Chr.12

Chr.16

Chr.14

Chr.11

Chr.19

Chr.X

Chr.8

Chr.18

Chr.9

Chr.17

Chr.13

Chr.10

Chr.15

Chr. 10 haplotypes

BALB/cByJ

A/J

DBA/2J

C3H/HeJ

C57BL/6J

129/SvImJ

0

10

20

30

40

50

60

70

80

90

100

110

120

130

Pos, Mbp

Genome-wide SNP Density

slide9

Chr. 12

290 SSLPs

15 SSLPs(2)

39 SSLPs(4+)

BALB/cByJ

A/J

0

22.8

45.6

68.4

91.2

114

BALB/cByJ

A/J

165 loci

Pos, Mbp

Chr. 5

436 SSLPs

25 SSLPs(2)

73 SSLPs(4+)

BALB/cByJ

A/J

0

29.7

59.4

89.1

118.8

148.5

BALB/cByJ

A/J

227 loci

Pos, Mbp

Distribution of SNPs and SSLPs

For two strains (A/J/BALB/cByJ), with 1112 randomly distributed SNPs the

mean expected block length is 2.3Mb. Probability of the largest block

40Mb (2.8e-5), 60Mb (4.2e-9), 80Mb (6.4e-13),100Mb (9.6e-17)

  • Co-distribution of SNPs and SSLPs
  • Chr. 5 contains many short blocks of common and disparate haplotypes
  • also shows a co-distribution of SSLPs and SNPs. In 5, 2, and 0.5 Mb bins
  • co-distribution of bins was evaluated (1-P=10-27, 10-24 and 7.4x10-11)
slide10

Utility of Mouse Haplotype Map

Chr. 10 haplotypes

  • Mapped mutant to 20MB region on MMU10
  • Shared haplotype made identifying new markers difficult
  • Used haplotype map to identify most compatible mapping partner for narrowing region
slide11

Extending the Haplotype Map to the Phenome Project

A/J LP/J

AKR/J MA/MyJ

BALB/cByJ MAI/Pas

BTBR MOLF/Ei

BUB/BnJ MSM/Ms

C3H/HeJ NOD/LtJ

C57BL/10J NON/LtJ

C57BL6J NZB/BlNJ

C57BLKS/J NZW/LacJ

C57BR/cdJ PERA/Ei

C57L/J PL/J

C58/J PWD/Ph

CAST/Ei RIIIS/J

CBA/J SEA/GnJ

CE/J SEG/Pas

CZECHII/Ei SJL/J

DBA/1J SM/J

DBA/2J SPRET/Ei

DDK/Pas ST/bJ

FVB/NJ SWR/J

I/LnJ WSB/Ei

JF1/Ms ZALENDE/Ei

KK/HlJ 129S1/SvImJ

LG/J 129X1/SvJ

Beck et al., Nature Genetics (2000) vol. 1, 23–25

slide12

Initial Set Selection

  • Goal – To pick an evenly spaced SNP set from the Celera collection that are from unique haplotypes and not recent strain specific mutations
  • Preference was given to SNPs where each allele was found in two strains (DBA, 129X1, A/J, B6)
  • Worked on assumption that selection criteria would favor older SNPs – musculus vs. domesticus
slide13

Initial Set Make-up

  • Initial design produced nearly 5000 assays
  • 941 SNPs represent cSNPs (splice site, mis-sense, or nonsense mutations)
  • 1 gap bigger than
  • 5MB
  • Biggest Gap –
  • 7.4MB on MMUX
slide14

Preliminary Data from SNP Assays

  • Over 2300 SNP assays contain data for 90% of DNAs – Over 4500 assays contain data for at least 24 of the strains
  • Average of 1200 SNPs found between any 2 strain pair combinations
  • Average SNP frequency of roughly 40% in pairwise comparisons
slide15

C57 Breeding History

MA/MyJ

C57BR

C57BL/6

C57BL/10

C58/J

C57L/J

C57BLKS

Beck et al., Nature Genetics (2000) vol. 1, 23–25

slide16

Comparison of SNP-based Clustering to Breeding History

MA/MyJ

MA/MyJ

C57BR

C58/J

C57BL/10

C57BL/6

C58/J

C57L/J

C57L/J

C57BR

C57BLKS

C57BL/10

C57BL/6

C57BLKS

Beck et al., Nature Genetics (2000) vol. 1, 23–25

slide17

SNP Data Detects Common Heritage

Beck et al., Nature Genetics (2000) vol. 1, 23–25

slide18

Prager et al. (1998) Mouse Genetics and Phylogeography

Relationship of Wild-derived Mouse Strains

M.m. musculusM.m. molossinusM.m. domesticusM.m. castaneusM. spretus

CZECHII/Ei JF1 PERA/Ei CAST/Ei SPRET/Ei

MAI/Pas MSM/Ms WSB/Ei SEG/Pas

PWD/PH MOLF/Ei ZALENDE/Ei

slide19

Wade et al. (2003) Nature 420, 574-578

Silver (1995) Mouse Genetics: Concepts and Applications

Ogura et al. (2003) Genomics 81, 369-377

Lack of Diversity Between M.m. musculus and M.m. molossinus

SNP Frequency

M.m. musculus

M.m. musculus

M.m. molossinus

M.m. molossinus

M.m. molossinus

M.m. musculus

slide20

?

M.m. domesticus

A Domesticus Haplotype

SNP Frequency

M.m. domesticus

M.m. domesticus

M.m. musculus

M.m. domesticus

US

Switz.

Peru

slide21

Future Steps

  • Do survey sequencing of wild-derived strains to assess true diversity
  • Continue to fill in gaps in data set and continue to expand SNP collection
  • Attempt to use data set to map phenotypic variants
slide22

Acknowledgements

Tim Wiltshire

Whitney Barnes

Patrick Merritt

Candace Motta Franzmarie Lippincott

Deborah Stradley

Niusha Ziaee

Serge Batalov

Steve Kay