AIP RESEARCH REPORT
Updated Dec. 1, 2018
Haplotype tests for recessive disorders
that affect fertility and other traits
J.B. Cole, P.M. VanRaden, D.J. Null, J.L. Hutchison, T.A. Cooper, and S.M. Hubbard
Animal Improvement Program, Animal Genomics and Improvement Laboratory, Agricultural Research
Service, USDA, Beltsville, MD 20705-2350
301-504-8334 (voice) ~ 301-504-8092 (fax) ~ firstname.lastname@example.org
This report was based on the UMD3.1 assembly for the bovine genome and has been replaced by AIP Research Report Genomic4, which gives locations based on the ARS-UCD genome assembly.
Haplotype tests now are used routinely to identify new recessive disorders and to track the carrier status of genotyped animals. Changes in the reporting of recessive factors that affect fertility and stillbirth recently have been described in detail (VanRaden et al., 2013)
. Carrier status for Holstein haplotypes with mutations for bovine leucocyte adhesion deficiency (BLAD; haplotype HHB), complex vertebral malformation (CVM; haplotype HHC), deficiency of uridine monophosphate synthase (DUMPS; haplotype HHD), mulefoot (syndactyly; haploptype HHM), polledness (haplotype HHP), red coat color (haplotypes HBR, HDR, and HHR), and cholesterol deficiency (HCD) now are reported in the XML files distributed by the Council on Dairy Cattle Breeding
. Brown Swiss haplotype tests for spinal dismyelination (SDM; haplotype BHD), spinal muscular atrophy (SMA; haplotype BHM), and Weaver Syndrome (haplotype BHW) also are provided, but those tests do not directly include the causative mutation as an additional single nucleotide polymorphism because too few bulls were previously tested; a haplotype for polledness (BHP) also is reported. An exact test of the loss-of-function (LOF) mutation within a haplotype that affects fertility in Jerseys (haplotype JH1) now is used to determine carrier status for genotyped Jerseys, and another Jersey haplotype that affects fertility (JH2) also was discovered (Van Raden et al., 2014
); a haplotype for polledness (JHP) also is reported. A haplotype that affects conception rate in Ayrshires (AH1) is now reported (Cooper et al., 2014
), and a new Ayrshire haplotype that affects fertility (AH2) was discovered (Null et al., 2017
The table below lists all of the recessive haplotypes currently tracked in the U.S. genomic evaluation system, the frequency of the minor (less common) haplotype, and the location in base pairs (bp) of the haplotype. Locations are exact (single bp) when the causative mutation is known and approximate (range of bp) when it is unknown, a duplication, a deletion, or multiple mutations. The frequency of carriers in the population is generally twice the haplotype frequency because carriers have 1 defective and 1 normal haplotype.
||Cooper et al. (2014), Venhoranta et al. (2014)
||Null et al. (2017)
||42,811,272 – 47,002,161
||VanRaden et al. (2011)
||Schwarzenbacher et al. (2016)
||Hafner et al. (1993), Thomsen et al. (2010)
|| 62,118,139 – 62,156,760
||El-Hamidi et al. (1989), Krebs et al., 2007
||1,705,834 – 1,989,480
|| Medugorac et al. (2012), Rothammer et al. (2014)
||McClure et al. (2013), Kunz et al., 2016
||Black/red coat color/
|| 14,757,332 – 14,759,082
||Lawlor et al. (2014)|
||Kipp et al. (2015), Charlier (2016), Menzi et al. (2016), Schütz et al. (2016)|
||Dominant red coat color
|| Capitan et al. (2014), Lawlor et al. (2014), Dorshorst et al., 2015||HH0
||21,184,869 – 21,188,198
||Agerholm et al. (2006), Charlier et al. (2012)
||Adams et al. (2012)
||94,860,836 – 96,553,339
||VanRaden et al. (2011), McClure et al. (2014)
||Daetwyler et al. (2014), McClure et al. (2014)
||Fritz et al. (2013)
||93,223,651 – 93,370,998
||Cooper et al. (2013), Schütz et al. (2016)
||Shuster et al. (1992)
||Agerholm et al. (2001)
||Shanks et al. (1984)
||77,663,790 – 77,701,209
||Eldridge et al. (1951), Duchesne et al. (2006)
|| Medugorac et al. (2012), Rothammer et al. (2014)
||Red coat color/
||Joerg et al. (1996)
||Sonstegard et al. (2013)
||8,812,759 – 9,414,082
||VanRaden et al. (2014)|
|| Medugorac et al. (2012), Rothammer et al. (2014)
|1Online Mendelian Inheritance in Animals (OMIA) identification number for Bos taurus (National Center for Biotechnology Information species code 9913).
Recessives with very low frequencies (e.g., HH4)
can be identified because many Holsteins have been genotyped (current exact
counts of genotyped animals are shown in the Council
on Dairy Cattle Breeding's "Genotype
Counts by Chip Type, Breed Code, and Sex Code
recessives in breeds with fewer genotyped animals and smaller populations
will not be detected until they have a high frequency in the population.
Haplotype tests are less accurate than LOF mutation tests, and retesting
valuable animals that have been identified as carriers using a haplotype
test is recommended if an exact test is available. Further information
on combining LOF mutation tests with haplotype tests is available (VanRaden et al., 2012)
as is further detail on genetic defects (Nicholas and Hobbs, 2014
; OMIA - Online Mendelian Inheritance in Animals, 2014
Adams, H.A., T. Sonstegard, P.M. VanRaden, D.J. Null, C. Van Tassell,
and H. Lewin. 2012. Identification of a nonsense mutation in APAF1 that is causal for a decrease in reproductive efficiency in dairy cattle
Plant Anim. Genome XX Conf., abstr.
Agerholm, J.S., C. Bendixen, O. Andersen, and J. Arnbjerg. 2001. Complex
vertebral malformation in Holstein calves
. J. Vet. Diagn. Invest.
Agerholm, J.S., F. McEvoy, and J. Arnbjerg. 2006. Brachyspina syndrome in a
. J. Vet. Diagn. Invest. 18:418–422.
Capitan, A., P. Michot, F. Guillaume, C. Grohs, A. Djari, S. Fritz, S. Barbey, P. Otz, E. Bourneuf, D. Esquerré, Y. Gallard, C. Klopp, and D. Boichard. 2014. Rapid discovery of mutations responsible for sporadic dominant genetic defects in livestock using genome sequence data: Enhancing the value of farm animals as model species
. Proc. 10th World Congr. Genet. Appl. Livest. Sci., Commun. 182.
Charlier, C. 2016. The role of mobile genetic elements in the bovine genome
. Plant Anim. Genome XXIV Conf., abstr. W636.
Charlier, C., J.S. Agerholm, W. Coppieters, P. Karlskov-Mortensen, W. Li, G. de Jong, C. Fasquelle, L. Karim, S. Cirera, N. Cambisano, N. Ahariz, E. Mullaart, M. Georges, and M. Fredholm. 2012. A deletion in the bovine FANCI gene compromises fertility by causing fetal death and brachyspina
. PLoS ONE
Cooper, T.A., G.R. Wiggans,
D.J. Null, J.L. Hutchison, and J.B. Cole. 2014. Genomic evaluation, breed identification, and discovery of a haplotype affecting fertility for Ayrshire dairy cattle
. J. Dairy Sci. 97:3878–3882.
Cooper, T.A., G.R. Wiggans, P.M. VanRaden, J.L. Hutchison, J.B. Cole, and
D.J. Null. 2013. Genomic evaluation of Ayrshire dairy cattle and new
haplotypes affecting fertility and stillbirth in Holstein, Brown Swiss and
. Amer. Dairy Sci. Assoc.–Amer. Soc. Anim. Sci. joint annual meeting, Indianapolis, IN, July 9, poster T206.
Daetwyler,H.D., A. Capitan, H. Pausch, P. Stothard, R. van Binsbergen, R.F. Brøndum, X. Liao, A. Djari, S.C. Rodriguez, C. Grohs, D. Esquerré, O. Bouchez, M.-N. Rossignol, C. Klopp, D. Rocha, S. Fritz, A. Eggen, P.J. Bowman, D. Coote, A.J. Chamberlain, C. Anderson, C.P. Van Tassell, I. Hulsegge, M.E. Goddard, B. Guldbrandtsen, M.S. Lund, R.F. Veerkamp, D.A. Boichard, R. Fries, and B.J. Hayes. 2014. Whole-genome sequencing of 234 bulls facilitates mapping of monogenic and complex traits in cattle
. Nature Genet. 46:858–865.
Dorshorst, B., C. Henegar, X. Liao, M. Sällman Almén, C.-J. Rubin, S. Ito, K. Wakamatsu, P. Stothard, B. Van Doormaal, G. Plastow, G.S. Barsh, and L. Andersson. 2015. Dominant red coat color in Holstein cattle is associated with a missense mutation in the coatomer protein complex, subunit alpha (COPA) gene
. PLoS ONE 10:e0128969.
Duchesne, A., M. Gautier, S. Chadi, C. Grohs, S. Floriot, Y. Gallard, G. Caste, A. Ducos, and A. Eggen. 2006. Identification of a doublet missense substitution in the bovine LRP4 gene as a candidate causal mutation for syndactyly in Holstein cattle
. Genomics 88:610–621.
El-Hamidi, M., H.W. Leipold, J.G.E. Vestweber, and G. Saperstein. 1989. Spinal
muscular atrophy in Brown Swiss calves
. J. Vet. Med. A. 36:731–738.
Eldridge, F.E., W.H. Smith, and W.M. McLeod. 1951. Syndactylism in Holstein-Friesian
cattle: Its inheritance, description and occurrence
. J. Hered. 42:241–250.
Fritz, S., A. Capitan, A. Djari, S. C. Rodriguez, A. Barbat, A. Baur, C. Grohs, B. Weiss, M. Boussaha, D. Esquerré, C. Klopp, D. Rocha, and D. Boichard. 2013.
Detection of haplotypes associated with prenatal death in dairy cattle and
identification of deleterious mutations in GART, SHBG and SLC37A2
Hafner, A., E. Dahme, G. Obermaier, P. Schmidt, and G. Dirksen. 1993. Spinal
dysmyelination in new-born Brown Swiss x Braunvieh calves
. J. Vet. Med. B
Joerg, H., H.R. Fries, E. Meijerink, and G.F. Stranzinger. 1996. Red
coat color in Holstein cattle is associated with a deletion in the MSHR
. Mamm. Genome 7:317–318.
Kipp, S., D. Segelke, S. Schierenbeck, F. Reinhardt, R. Reents, C. Wurmser, H. Pausch, R. Fries, G. Thaller, J. Tetens, J. Pott, M. Piechotta, and W. Grünberg. 2015. A new Holstein haplotype affecting calf survival
. Interbull Bull. 49:49–53.
I. Medugorac, S. Röther, K. Strässer, and M. Förster. 2007. A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy
. Proc. Natl. Acad. Sci. USA 104:6746–6751.
Kunz, E., S. Rothammer, H. Pausch, H. Schwarzenbacher, F. Seefried, K. Matiasek, D. Seichter, I. Russ, R. Fries, and I. Medugorac. 2016. Confirmation of a non-synonymous SNP in PNPLA8 as a candidate causal mutation for Weaver syndrome in Brown Swiss cattle
. Genet. Sel. Evol. 48:21.
Lawlor, T.J., P.M. VanRaden, D. Null, J. Levisee, and B. Dorhorst. 2014.
Using haplotypes to unravel the inheritance of Holstein coat color
. Proc. World Congr. Genet. Appl. Livest. Prod., Commun. 289.
McClure, M., E. Kim, D. Bickhart, D. Null, T. Cooper, J. Cole, G.
Wiggans, P. Ajmone-Marsan, L. Colli, E. Santus, G.E., Liu, S.
Schroeder, L. Matukumalli, C. Van Tassell, and T. Sonstegard. 2013.
mapping for Weaver Syndrome in Brown Swiss cattle and the identification
of 41 concordant mutations across NRCAM, PNPLA8 and CTTNBP2
McClure, M.C., D. Bickhart, D. Null, P. VanRaden, L. Xu, G. Wiggans, G. Liu, S. Schroeder, J. Glasscock, J. Armstrong, J.B. Cole, C.P. Van Tassell, and T.S. Sonstegard. 2014. Bovine exome sequence analysis and targeted SNP genotyping of recessive fertility defects BH1, HH2, and HH3 reveal causative mutation in SMC2 for HH3
. PLoS ONE 9:e92769.
Medugorac, I., D. Seichter, A. Graf, I. Russ, H. Blum, K.H. Göpel, S. Rothammer, M. Förster, and S. Krebs. 2012. Bovine polledness – An autosomal dominant trait with allelic heterogeneity
. PLoS ONE 7:e39477.
Menzi, F., N. Besuchet-Schmutz, M. Fragnière, S. Hofstetter, V. Jagannathan, T. Mock, A Raemy, E. Studer, K. Mehinagic, N. Regenscheit, M. Meylan, F. Schmitz-Hsu, and C. Drögemüller. 2016. A transposable element insertion in APOB causes cholesterol deficiency in Holstein cattle
. Anim. Genet. 47:253–257
Nicholas, F.W., and M. Hobbs. 2014. Mutation discovery for Mendelian traits in non-laboratory animals: A review of achievements up to 2012
. Anim. Genet. 45:157–170.
Null, D.J., J.L. Hutchison, D.M. Bickhart, P.M. VanRaden, and J.B. Cole. 2017. Discovery of a haplotype affecting fertility in Ayrshire dairy cattle and identification of a putative causal variant
. J. Dairy Sci.100(Suppl. 2):199(abstr. 206).
OMIA - Online Mendelian Inheritance in Animals
. 2014. Fac. Vet. Sci., Univ. Sydney.
Rothammer, S., A. Capitan, E. Mullaart, D. Seichter, I. Russ, and I. Medugorac. 2014. The 80-kb DNA duplication on BTA1 is the only remaining candidate mutation for the polled phenotype of Friesian origin
. Genet. Sel. Evol. 46:44.
Schütz, E., C. Wehrhahn, M. Wanjek, R. Bortfeld, W.E. Wemheuer, J. Beck, and B. Brenig. 2016. The Holstein Friesian lethal haplotype 5 (HH5) results from a complete deletion of TFB1M and cholesterol deficiency (CDH) from an ERV-(LTR) insertion into the coding region of APOB
. PLoS ONE 11:e0154602.
Schwarzenbacher, H., J. Burgstaller, F.R. Seefried, C. Wurmser, M. Hilbe, S. Jung., C. Fuerst, N. Dinhopl, H. Weissenböck, B. Fuerst-Waltl, M. Dolezal, R. Winkler, O. Grueter, U. Bleul, T. Wittek, R. Fries, and H. Pausch. 2016. A missense mutation in TUBD1 is associated with high juvenile mortality in Braunvieh and Fleckvieh cattle
. BMC Genomics 17:400
Shanks, R.D., D.B. Dombrowski, G.W. Harpestad, and J.L. Robinson. 1984. Inheritance of
UMP synthase in dairy cattle
. J. Hered. 75:337–340.
Shuster, D.E., M.E. Kehrli Jr., M.R. Ackermann, and R.O. Gilbert.
1992. Identification and prevalence of a genetic defect that causes
leukocyte adhesion deficiency in Holstein cattle
. Proc. Natl. Acad. Sci.
Sonstegard, T.S., J.B. Cole, P.M. VanRaden, C.P. Van Tassell, D.J., Null,
S.G. Schroeder, D. Bickhart, and M.C. McClure. 2013. Identification
of a nonsense mutation in CWC15 associated with decreased reproductive
efficiency in Jersey cattle
. PLoS ONE 8:e54872.
Thomsen, B., P.H. Nissen, J.S. Agerholm, and C. Bendixen. 2010. Congenital bovine spinal dysmyelination is caused by a missense mutation in the SPAST gene
. Neurogenetics 11:175–183.
VanRaden, P., D. Null, J. Hutchison, D. Bickhart, and S. Schroeder. 2014. Jersey haplotype 2 (JH2)
. Changes to evaluation system (August 2014). Council on Dairy Cattle Breeding.
VanRaden, P., D. Null, J. Hutchison, and T. Cooper. 2013. New fertility and stillbirth haplotypes and changes in haplotype status
. Changes to evaluation system (August 2013). Council on Dairy Cattle Breeding.
VanRaden, P.M., D.J. Null, T.S. Sonstegard, H.A. Adams, C.P. Van Tassell,
and K.M. Olson. 2012. Fine mapping and discovery of recessive
mutations that cause abortions in dairy cattle
. J. Dairy Sci. 95(Suppl. 2):ii–iii(abstr. LB6).
VanRaden, P.M., K.M. Olson, D.J. Null, and J.L. Hutchison. 2011. Harmful
recessive effects on fertility detected by absence of homozygous
. J. Dairy Sci. 94:6153–6161.
Venhoranta, H., H. Pausch, K. Flisikowski, C. Wurmser, J. Taponen, H. Rautala, A. Kind, A. Schnieke, R. Fries, H. Lohi, and M. Andersson. In frame exon skipping in UBE3B is associated with developmental disorders and increased mortality in cattle
. BMC Genomics 15:890.