AIP RESEARCH REPORT GENOMIC3 (09-13) 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) ~ john.cole@ars.usda.gov ~ http://aipl.arsusda.gov/ This report was based on the UMD3.1 assembly for the bovine genome and has been replaced by AIP Research Report Genomic4, which gives locations based on the ARS-UCD genome assembly.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.

Breed	Haplotype	OMIA 9913 ID1	Functional/ gene name	Frequency (%)	Chromosome	Region (bp)	Reference
Ayrshire	AH1	001934	PIRM/UBE3B	13.0	17	65,921,497	Cooper et al. (2014), Venhoranta et al. (2014)
	AH2	002134	RPAP2	9.8	3	51,267,548	Null et al. (2017)
Brown Swiss	BH1	001825	—	6.67	7	42,811,272 – 47,002,161	VanRaden et al. (2011)
	BH2	001939	TUBD1	7.78	19	11,063,520	Schwarzenbacher et al. (2016)
	BHD	001247	SDM/SPAST	2.19	11	14,742,058	Hafner et al. (1993), Thomsen et al. (2010)
	BHM	000939	SMA/KDSR(FVT1)	3.61	24	62,118,139 – 62,156,760	El-Hamidi et al. (1989), Krebs et al., 2007
	BHP	000483	Polledness/POLLED	0.4	1	1,705,834 – 1,989,480	Medugorac et al. (2012), Rothammer et al. (2014)
	BHW	000827	Weaver/PNPLA8	1.56	4	49,878,773	McClure et al. (2013), Kunz et al., 2016
Holstein	HBR	001199	Black/red coat color/ MC1R(MSHR)	0.8	18	14,757,332 – 14,759,082	Lawlor et al. (2014)
	HCD	001965	Cholesterol deficiency/APOB	2.5	11	77,958,995	Kipp et al. (2015), Charlier (2016), Menzi et al. (2016), Schütz et al. (2016)
	HDR	001529	Dominant red coat color	0.04	3	9,479,761	Capitan et al. (2014), Lawlor et al. (2014), Dorshorst et al., 2015
	HH0	000151	Brachyspina/FANCI	2.76	21	21,184,869 – 21,188,198	Agerholm et al. (2006), Charlier et al. (2012)
	HH1	000001	APAF1	1.92	5	63,150,400	Adams et al. (2012)
	HH2	001823	—	1.66	1	94,860,836 – 96,553,339	VanRaden et al. (2011), McClure et al. (2014)
	HH3	001824	SMC2	2.95	8	95,410,507	Daetwyler et al. (2014), McClure et al. (2014)
	HH4	001826	GART	0.37	1	1,277,227	Fritz et al. (2013)
	HH5	001941	TFB1M	2.22	9	93,223,651 – 93,370,998	Cooper et al. (2013), Schütz et al. (2016)
	HHB	000595	BLAD/ITGB2	0.25	1	145,119,004	Shuster et al. (1992)
	HHC	001340	CVM/SLC35A3	1.37	3	43,412,427	Agerholm et al. (2001)
	HHD	000262	DUMPS/UMPS	0.01	1	69,757,801	Shanks et al. (1984)
	HHM	000963	Mulefoot/LRP4	0.07	15	77,663,790 – 77,701,209	Eldridge et al. (1951), Duchesne et al. (2006)
	HHP	000483	Polledness/POLLED	0.71	1	1,705,834– 1,989,480	Medugorac et al. (2012), Rothammer et al. (2014)
	HHR	001199	Red coat color/ MC1R(MSHR)	5.42	18	14,758,207	Joerg et al. (1996)
Jersey	JH1	001697	CWC15	12.10	15	15,707,169	Sonstegard et al. (2013)
	JH2	001942	—	1.3	26	8,812,759 – 9,414,082	VanRaden et al. (2014)
	JHP	000483	Polledness/POLLED	2.2	1	1,705,834– 1,989,480	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"). Generally 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).

References

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