New use for genomics: “Haplotypes affecting fertility”

New use for genomics: “Haplotypes affecting fertility”

by Bennet Cassell
The author is a retired extension dairy scientist in genetics and management and professor emeritus at Virginia Tech, Blacksburg

Some new uses for genomics data were reported at the ADSA meetings in New Orleans, La., this July. Scientists at AIPL searched through genomic databases to find “haplotypes” that existed at relatively high frequencies but never paired with another copy of the same haplotype.

Animals that carry such haplotypes as heterozygotes appear normal. But, if mated to another carrier, one in four progeny would inherit two copies of the suspect haplotype and not survive long enough to be born to even have a genomic test. In fact, many such individuals could be lost very early in gestation.

What is a haplotype?
A haplotype is a segment of the single strand of DNA that parents pass to offspring through egg and sperm cells. Scientists detect haplotypes by combining genomic tests of progeny and parents.

The 50K SNP chip (and the other versions) measure nucleic acid pairs from both strands of DNA at specific sites in the genome. Computer programs sort out which single-stranded segments of DNA came from each parent and store the haplotypes observed in a record of the parent(s) of genomically tested animals.

Haplotypes from a single individual can vary because of “crossovers” between the two strands of DNA in an animal’s genome. Crossovers rearrange the sequence of base pairs, creating new haplotypes that may persist for generations. The average rate for crossovers is once for each of 29 chromosomes (plus sex chromosomes) in formation of each sperm and egg cell in dairy cattle.

Nature can generate a great deal of genetic variation through formation of sperm and egg cells, as there are many haplotypes in each one! However, individual haplotypes are transmitted fairly consistently to offspring.

Haplotypes sometimes include gene sequences that behave much like the single or very tightly linked genes that control traits like horned-polled, CVM carrier or CVM free, and so forth. The new method detects genetic sequences that only exist in the heterozygous form. Effects of the homozygous condition for reported sequences have not been observed, likely because of early embryonic or fetal death.

The study identified three haplotypes in Holsteins and one each in Jerseys and Brown Swiss. Odds that the missing combinations exist but simply haven’t been seen in genomic-tested animals are under 0.02 percent. That is so low that we can conclude that homozygous combinations never progressed far enough to be genomically tested.

We have names for observed, unfavorable phenotypes like CVM, BLAD, and, most recently, Brachyspina. The five new discoveries are designated differently, JH1, BH1, HH1, HH2, and HH3.

The JH1 designation means “Jersey haplotype 1,” since it is the first haplotype discovered in Jerseys that is not associated with an already named condition, and it only exists in heterozygous form.

The findings reported at ADSA were confirmed using the national database for service sire conception rate (SCR) and sire stillbirth rate (SSB). The report compared matings for conception rate or births for stillbirths where the service sire and the maternal grandsire (sire of the mate) were carriers of one of the five haplotypes.

Each service sire or maternal grandsire in the SCR or SSB databases fell into one of three categories:
• tested noncarrier
• tested carrier
• not tested

This produced nine combinations for each service sire-maternal grandsire combination for conception rate or stillbirth records. The carrier-MGS carrier combinations reduced conception rates by -3.1 to -3.7 percent. For comparison, service sire-MGS CVM carriers which were identified by the test used for several years in the industry reduced conception rate by -2.9 percent. The new haplotype effect was slightly less than expected from haplotype frequencies in the population. However, it still showed that such matings had an economic effect at the farm level.

Stillbirths unaffected, but
Stillbirths were unaffected by the carrier sire-carrier MGS category. This result suggests that losses for these five haplotypes occur earlier in gestation rather than at or immediately after birth.

There are quite a few carriers in the three breeds. The breed associations have taken very progressive positions in revealing this new information. The August 2011 Holstein Redbook will list carriers. Check the breed websites for links to more information. For a scientific study reported in early July, the response has been immediate and impressive.

For now, these five haplotypes will be called “haplotypes affecting fertility.”

Frequency of carriers, as reported in the scientific manuscript, exceeds 20 percent for JH1 and has for a number of years. BH1 exists in 16 percent of tested Brown Swiss animals and has been going up for 35 years. The Holstein haplotypes are less frequent, 2.7 to 6.4 percent, with the two most frequent haplotypes rising in frequency over the past 10 years.

The HH3 haplotype is the most frequent among top 100 Net Merit and TPI Holstein bulls, with 12 and 20 carriers, respectively, based on April evaluations. The JH1 haplotype appears in 21 and 24 of the top 100 Jerseys for Net Merit and JPI, respectively.

Must exist for years
This detection method requires that the haplotype exist in a population for a number of years. The earliest carriers of all haplotypes tested were born prior to 1980. More widespread genomic testing will improve this procedure. That means we can expect that several more such undetected haplotypes will be found in the future. Carrier-carrier matings will affect conception rate of the mating and will preserve an unfavorable haplotype in two-thirds of matings that succeed.

Dairy farmers should remain vigilant for possible dysfunctional phenotypes in their herds. The genomic test, however, finds problems that prevent expression of any phenotype. This new discovery is another reason to embrace widespread genomic testing of dairy animals.

This article appeared on age 528 of the August 25, 2011 issue of Hoard's Dairyman