Q + A: Epimutations AND Negative Consequences of ART

POLICY CONSIDERATIONS FOR THE INTERNATIONAL YAK ASSOCIATION (IYAK)

May 21, 2018 

by Nicole Porter, PhD

 

"The time has come for ethics to be removed from the hands of the philosophers and biologisized.Look closely at nature. Every species is a masterpiece, exquisitely adapted to the particular environment in which it has survived. Who are we to destroy or even diminish biodiversity?"

 - E.O. Wilson, Sociobiology

SUMMARY 

Purpose. 1) We make an effort to explain epimutations and the negative consequences of Artificial Reproductive Technologies (ART) in a way that is accessible to anyone interested in the topic, but is also comprehensive enough to satisfy those who are skeptical or unfamiliar with epigenetics. 2) Also, it is the Industry Standard for professional Breed Associations to have a regulatory policy regarding ART. The Secondary goal here is to inform performance-oriented policies for ART. Recommendations are made based on other breed associations' Best Practices and current knowledge of ART in North American Yak (NAY). 3) Finally, it appears evident that we should do no harm - and should not jump the gun on this issue. If we are uncertain and risk is indicated, the safe and responsible approach would be to wait to include these animals in the breed book until more data and information is available.

Conclusions.

1) ART has Negative Consequences and Poses Health Risks to NAY:  

  • Expert Warnings: Experts in ART are cautioning us about the risks and deleterious effects.
  • Extensive Research: There is ample research evidence (e.g. negative prenatal and neonatal effects, as well as adolescent, adult, and transgenerational consequences).
  • Current Negative Consequences: We’re currently seeing these consequences in our NAY. 
  • Anticipated Consequences: We can assume negative effects will continue into adulthood and future generations as predicted by research. 

2) Best Practices indicate ART should be Preformed by Professionals: Given that we know ART causes dangerous Epimutations, with negative consequences to the health of the animal, the offspring, and the NAY herd as a whole. It would be irresponsible not to regulate the use of these technologies and adopt methodologies that have been successful in other associations: 

  • Required Genetic Centers: It's safer and appropriate to adopt the industry standard of the use Genetic Centers to extract semen from bulls.
  • Required Qualified Technicians: It is a Best Practice and industry norm to use trained professionals and veterinarians to in inseminate cows.

We should be cautious and thoughtful in our adoption of questionable technology and learn from the mistakes of other Industries and breed associations. ART is at worst, fatal - at best, unnecessary. The immediate need is to create a policy that protects the safety of the animals undergoing the procedures: 1) use of Genetic Centers and 2) Qualified Technicians.

3) ART should be Evaluated in NAY: At the very least, more research is necessary on ART before we consider these few animals and new procedures safe for inclusion in our herd book and breeding stock. We should research and evaluate the consequences of ART (with transparency) over time in NAY. There is no rush to register AI calves; there is no reason to exclude them if they grow to be healthy, with no negative consequences are found. There is no reason to quickly include them if negative consequences are shown to be observable and statistically significant. 

 

Introduction to Epimutations

What are Epimutations?

We all know mutations are changes to DNA sequence (like "AATG" becomes "ATAG"). Epimutations are also genetic disorders and represent powerful changes to gene function. The difference is that Epimutations occur by gene-activation - turning on and off genes. (AATG gets activated when it shouldn't). They are still inherited through the sperm and egg, but don't involve changes in sequencing (Wu, 2001). Epigenetics is pretty straight forward.

Why is negative ART research ignored? 

  • Technophiles: I recently asked Dr. Betsy Dresser why, after 50 years of research, it is so hard to get breeders and veterinarians to understand the problems with ART? She said: 

“It has always been tough to get an ear with the cowboys. They want what's simplest and they have always wanted everyone to know that they had chosen the lead horse, so to speak, in whatever advancements come along!  Thus, biotechnology.”

                                                                                                          - Dr. Betsy Dresser

  • Epigenetics isn't taught: Yes, Epigenetic is newer than Mendelian genetics. Mendel died in 1884; Waddington coined "epigenetics" in 1942. But that's not it. Physicians and veterinarians educate their clients; not researchers. While MDs, Doctor of Veterinary Medicine and Veterinariae Medicinae Doctoris are currently being trained in epigenetics - it is nominal. There is still a gap in their education, appropriately emphasizing practical application. Researchers get to study, while MDs, DVMs and even VMDs are in residency and learning practical application in rotation. After years of eduction, no PhD is trained to reach in a cow or even take a babies temp - but we spent those years doing and read research. It changes perspective. 

ART Epimutations in Prenatal Development? (many already demonstrated in NAY)

  1. Large Offspring Syndrome (LOS) (n=1)
  2. Maternal Dysfunction/Reproductive Incompetence (n=1)
  3. Infant/Neonatal Mortality (n=1)
  4. Delivery Complications (n>1)
  5. Preterm Birth (n=1)*
  6. Pregnancy Complications: miscarriage, ectopic, etc. (est. >88)**
  7. Homozygosity, attempted inseminations from same bull/year (est. >45)*
  8. Congenital Malformation (n=?)*
  9. Transmission of DNA Sequencing “Genetic” Disorders (unknown)*

* Due to our researchers’ lack of transparency, we do not know exactly how many calves were already registered, survived birth, or were attempted. From various sources, there is: 1 known 2017 registration, at least 4 that survived birth this season, and an estimated over 88 failed pregnancies. 

** Given the methodology being used (repeated trials ending when the cow has stopped cycling), it seems clear these events are due to pregnancy complications, not lack of conception.

Because we have evidence that ART is functioning predictably so far, it supports the expectation that the widely-documented complications and negative consequences will occur in yak offspring as they mature. 

ART Epimutation Consequences to Offspring? (should be evaluated in NAY)

  1. Early Delays in Growth  
  2. Developmental Incompetence
  3. Negative Health Effects: Increased cancer, diabetes, genetic diseases
  4. Changes to Maturation Timing 
  5. Maternal Reproductive Incompetence at maturity
  6. Decreased Cognitive Abilities
  7. Dysfunctional Social Behavior 
  8. Decreased Maternal Competence
  9. LOS inherited by future generations 

ART Epimutation Consequences to Parents? (should be evaluated in NAY).

  1. Decreased Reproductive Competence
  2. Decreased Maternal Competence
  3. Increased Aggression  

AI calves should not be considered for registration until the repercussions of ART are available to transparent evaluation. 

These calves should be followed during development to inform our decision. 

 

 

  • Best Practices: Some of these ethical and health issues can be mitigated by the regulation of the semen collection and insemination process by professionals. These are the Industry Standard for many professional breed associations. 
    • Genetics Centers
    • Certified Technicians
  • ART Registration Solves Many Problems: Given the damaging consequences to offspring and future generations, we conclude that these animals should not be encouraged to interbreed with the Foundation herd. A separate registration book to accommodate ART offspring would solve these issues. These are: the issues mitigating both need and risk, considering equally the heath of the animal and the economic impact of ART to breeders.   
    • Geographic Limitations
    • Dangers of Heterozygosity 
    • Epimutations of Offspring
    • Transmission of Epimutations to Future Generations
    • Depreciation of the Quality of the Foundation Herd
    • Depreciation of the Economic Value of the Foundation Herd
    • Preservation of the Integrity of the Genetics of the NAY 
    • Ability of the ART Offspring to be Registered
    • Open Competition between Live-cover and ART offspring
    • Indication to Uninformed, Newcomers of Difference between ART and Live Breeding 
    • Facilitation of Research Comparing Effects of ART on NAY
    • Provides Freedom to Pursue Any Chosen Breeding Plan Desired
    • Responsibly Provides Opportunities for Furthering Research  

These rules and those policies that the Association’s Board may adopt from time to time relate to those abnormalities that are pathological conditions of genetic origin. These types of abnormalities have come to be referred to as “genetic conditions.”… can include an impairment of health or a condition of abnormal function due to an abnormal or mutated gene. Set forth below are descriptions of those conditions that the Association currently recognizes as “genetic conditions.” 

- Amended Angus Breed Association, 2012

BENEFITS OF ARTIFICIAL Reproductive Technology (ART) 

Genetic Diversity (Animal Conservation). One of the biggest challenges to breeding captive animals, like North American Yak (NAY), gorilla or wild antelope is the loss of genetic diversity due to inbreeding. However, researchers considered ART a last resort, because most researchers have concluded the health risks are too high (Association of Zoos and Aquariums, AZA).

Dr. Betsy Dresser only condones “the use of Any of these procedures to save endangered species.” She is responsible for 28 of the world’s Scientific Firsts. It is not justifiable where successful line-breeding is possible and ongoing, such as NAY (eg. where suitable mates are available, genetic defects are low or absent, and there is no evidence of loss of reproductive or phenotypic vigor). These indicators (vigor and absence of genetic disorder or disease) are also regarded the best measures of a populations health by genetics researchers (---). Dresser believes ART should always be avoided and is only justifiable to end extinction, as in her experiments:

  • the world’s first test tube gorilla
  • the first wild species kittens from embryo transfer
  • the first endangered antelope from AI and ET
  • the first cloned cats
  • AI used for the first successful reintroduction to the wild with sandhill cranes, etc.

Decreased Quarantine Risk. Artificial Insemination could also be used to overcome quarantine restrictions imposed by geographic limitations and the attendant risks of disease. In absence of suitable mates where genetic defects are evidenced, and there is measurable loss of reproductive or phenotypic vigor importing semen can preserve herd health. IYAK associates may be an example of this.


Genetic Dysfunction OF Artificial Reproductive Technology (ART)

Genetic Dysfunction. ART calves are genetically dysfunctional. They carry uncountable Epimutations, which are very similar to genetic mutations. These animals are not "genetically identical", genetical equal, or even genetically similar to live-cover counterparts in any way. 

Epimutuations are Simple to Understand and Easy to Explain: We are all familiar with Mutations (changes to the DNA sequence). Epimutations are just as bad, but represent changes to the way the gene functions. These molecular mutations are also inherited through the sperm and egg, but are not based on a changes in DNA sequence (Wu, 2001). You do not have to be a molecular geneticist to understand Epimutations cause genes turn on and off incorrectly. No one needs to understand aberrant methylation patterns to intelligently consider the negative consequences of ART. Researchers are not disputing these mechanisms. It's not fringe research. You can decide you don't care if there are consequences to NAY, but you cant decide ART is harmless just because others are misinformed or uneducated. 

Epimutations Are Mainstream: It is not controversial to say there is "a link between assisted reproductive techniques (ARTs) and [epimutations] imprinting disorders." A comprehensive paper discussing Epimutations in ART is: Epigenetics and assisted reproductive technology by  Iliadou, Janson, & Cnattinhjius (2011) from the Journal of Internal Medicine. 

Epimutations Cause Dysfunctional Health Problems: Problems resulting from ART are well established. This list is from 1988 by Dr. Betsy Dresser, in the landmark book Biodiversity by (Ed) EO Wilson (Wilson is a revolutionary giant, may be repressible for the rise of epigenetics, and is the subject of a wonderful recent PBS documentary "Of Ants and Men" There is a really interesting conversation on "religion" and tribalism here that may make a few folks laugh).

  • birth weight 

  • deficits in maternal postpartum behavior
  • placenta formation
  • rate of ovum transport
  • length of gestation 
  • deficits in neonatal behavior
  • transgenerational and intergenerational consequences for offspring

Epimutations in Cattle are Well Researched. Here is a comprehensive article addressing cattle: Epigenetic disorders and altered gene expression after use of Assisted Reproductive Technologies in domestic cattle (Urrego et al, 2014). Here is another: Turning-off of bovine imprinted genes SNRPN, H19/IGF2, and IGF2R due to artificial reproductive technologies (Smith LC, et al, 2015). 


Health risks OF Artificial Reproductive Technology (ART)

Cumulative Health Risk (100%). The original estimation of >68% using Baysian Probability analysis to calculate the cumulative health risk from the previously listed probabilities was appropriate use of statistics, but it was an understatement and oversimplification when compared to more comprehensive data. A more accurate estimation is actually >100%. I don't believe it is excessive to say, when all of the risks are taken together that many negative consequences will occur due to ART, as one continues research we begin to see it is "inevitable" that negative health consequences occur. These effects are passed to offspring and future generations. The more we examine the data the more apparent it becomes that dismissing these health concerns is unethical and irrational. 

  • Birthweight: Large Offspring Syndrome (LOS): According to Iiandou (2011) ART caused "Large offspring syndrome (LOS) ... is a well-known in cattle". "It is characterized by foetal overgrowth, breathing difficulties and sudden perinatal death." I have heard many cattlemen dismiss LOS as a mismatch between bull and cow. It is unfair to dismiss events and tell folk using ART "its the cows fault." AI makes Bigger calves. One recent ART yak cow had historically had big calves, but the ART calf was the one resulting in death. If you want bigger calves, breed them. Don't achieve it though genetic aberrations that will be passed on to future generations. 

    • ART increases oversized offspring (Young 2001) in cattle (Young, 1998, Smith, 1984).
    • LOS is passed on to offspring and future generations: If they live to breed, LOS and its developmental implications are transmitted to offspring in cattle (Wrenzycki et al, 2005; Perecin F, 2009). 
    • Offspring are Developmentally Dysfunctional: In cattle, offspring and grandchildren differ significantly in morphology and are developmental competence (Farin, 2006; Nowak-Imialek, 2008). 
  • Deficits in maternal postpartum behavior ART Causes Maternal Rejection. It is well known to captive breeders in zoos and reserves that there is a high rejection rate for animals conceived by ART (Dresser, 1998, Ross, 2005). It is also well known that prenatal stress and depression causes epimutations in rats, humans, and many other species . Maternal Rejection is a serious concern and real consequence. The Hill’s can be told “its the cow’s fault” and agree their cow was a “bad mom”, but did she cause calf deaths before AI? You cant justify it, ART causes many negative changes to maternal behavior, any disruption or insult at critical periods does. ART causes maternal rejection: AI turns poor moms, average moms and even good mom’s into bad moms. And whether you understand Epimutations or not, this is passed on to offspring (Dresser, 1998, Cameron, 2011, A Discover article on the work of Szyf and Meaney 2010-17). Maternal imprints and the origins of variation (Champagne, 2011). Paternal Influences on Offspring Development: Behavioural and Epigenetic Pathways from Journal of Nuroendocrinology. 

  • Epimutations from the Bull = Paternal Imprinting Defects: Cox, G. F. , Bürger, J. , Lip, V. , Mau, U. A. , Sperling, K. , Wu, B. L. , and Horsthemke, B. (2002). Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am. J. Hum. Genet. 71, 162–164. 
  • Epimutations from the Cow = Maternal Dysfunctional Reproductive Incompetence (placenta formation, rate of ovum transport, length of gestation): ART linked Reproductive Developmental Incompetence is widely demonstrated in mice (Vigone, 2015), vole and many other species such as humans (Hashimoto, 2009) and primates (Van Blerkom, 2004; Nusser, 2001) as well as bovine (Atkas et al., 1995; Bilodeau‐Goeseels 2011; Guixue et al., 2001; Luciano et al., 2004, Farin, 2006; Nowak-Imialek, 2008; Salhab et al., 2010).

Other Biological Health Effects of ART:

Biological Consequences are Major: "Work on animals, plants, and fungi now leaves little doubt that gene silencing is a major biological consequence of DNA methylation" (Colot and Rossignol 1999). "AI bypasses many of the normal steps involved in fertilization and activation of the oocyte" (Cox, 2002). ART causes dangerous epimutations: "Genomic Imprinting, DNA methylation is essential for development and plays an important role in inactivation of the X-chromosome and genomic imprinting" (Jaenisch 1997). "Epigenetic reprogramming throughout preimplantation development and consequences for assisted reproductive technologies (Wrenzycki et al, 2011).

  • Damage to Cell Structure Sperm and Egg undergoes mechanical stress, which may damage certain intracellular structures. The true impact on fertilization is unknown, but only 50% of conceptions are successful in humans, and animal studies indicate that other abnormalities may occur, including an alteration in calcium oscillations and delayed decondensation of sperm chromosomes. It is possible that AI disrupts the production or function of trans-acting factors or local structures necessary for imprinting of the maternal chromosome 15. (Augustin, R. , Pocar, P. , Wrenzycki, C. , Niemann, H. , and Fischer, B. (2003). Mitogenic and anti-apoptotic activity of insulin on bovine embryos produced in vitro. Reproduction 126, 91–99. 
  • Dyfunctional Embryonic Development Bartolomei, M. S. , and Tilghman, S. M. (1997). Genomic imprinting in mammals. Annu. Rev. Genet. 31, 493–525. 
  • Metabolic Changes: Cell Death and Insulin dysfunction AI causes other changes (e.g., the introduction of the acrosome and its digestive enzymes into the ooplasm). Changes in Insulin production, glucose, and interferon: insulin growth factors-1 and -2 (IGF-1 and -2), their receptors (IGF-1r and -2r), facilitative glucose transporters-1 and -3 (Glut-1 and -3), and interferon (Bertolini, M. , Beam, S. W. , Shim, H. , Bertolini, L. R. , Moyer, A. L. , Famula, T. R. , and Anderson, G. B. (2002). Growth, development, and expression by in vivo- and in vitro-produced day 7 and 16 bovine embryos. Mol. Reprod. Dev. 63, 318–328. 
  • Increases Cancer rates: The methylation of tumor suppressor gene promoters contributes directly to progression of some cancers (Jones and Laird 1999) Methylation-mediated silencing also plays a part in both the etiology of human disease and attempts at therapeutic intervention.
  • Causes Rare Genetic Diseases: through mutations in a methyl-CpG-binding protein (MeCP2; Amir et al. 1999) and the DNA methyltransferase DNMT3b (Okano et al. 1999, Garrick et al. 1998)
  • Impaired Intellectual disability, neurological impairment, and problems with movement and balance (ataxia) including Angelman syndrome, severe speech impediment in human children) Cox, G. F. , Bürger, J. , Lip, V. , Mau, U. A. , Sperling, K. , Wu, B. L. , and Horsthemke, B. (2002). Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am. J. Hum. Genet. 71, 162–164. 
  • It may also contribute to immobilization of mammalian transposons, suppression of transcriptional noise, and the control of tissue-specific gene expression. 
  • Increased Risk of All Transmitted Disease. If the bull is not properly tested, the spreading of genital diseases will be increased, not decreased, by AI. It has long been acknowledged and is well known, according to the Food and Agricultural Association of the United Nations (FAO), that disease risks to animal health from artificial insemination are increased in bovine semen testing (Eaglesome MD and Garcia MM, 1992). 
  • Bottle Feeding and Surrogate Rearing. The most successful bottle reared yak, and other human reared wild-types are dysfunctional from an animal behavior perspective. 1) there is a reduced ability to successfully integrate with the group (e.g herd, troop, etc). 2) There is an increased risk of poor maternal skills and inability to successfully rear their own offspring. 3) Epigenetics shows, cross-generational research in many species suggests that these deficits are transmitted inter-generationally with measurable consequences to grand and great-grand children. 
  • Miscarriage. It is estimated to occur approximately between 20-80% of the cases depending on species, most of which occur during early weeks of pregnancy. The less domesticated the animal, the less likely the pregnancy will be successful. According to the IYAK data many NA yak are closer to ancestral yak (est. ≈ 50%) than their domestic counter parts.
  • Ectopic Pregnancy. According to some statistics, there is a 4Xs greater chance (4 out of every 100) subjects undergoing AI may have an ectopic pregnancy, while its probability after natural insemination is .08%. 
  • Cow Allergies. It is possible to develop some kind of allergy to any component of the seminal lavage, although it is unlikely. In fact, this is probably the less common side effect found among subjects that have undergone AI.
  • Immune Reactions. Creation of antisperm-antibodies among those undergoing AI. The likelihood is <5 %.
  • Ovarian Lyperstimulation Syndrome (OHSS). Fairly uncommon but only resolved by cancelling the insemination cycle.
  • Multiple Births. This occurs between 12-30% of subjects. While normally conceived twins are of limited risk to the wellbeing of the mother and offspring, if the offspring are bred to be larger than the maternal line, or suffer from increased growth hormone due to acromegaly, this can be dangerous or fatal to the cow.

Other Precursors and causes to Epimutations from ART

Causes Dysfunctional Sexual Behavior in Cows. Academic research in this area suggest that AI causes dysfunctional sexual behavior in females of a variety of species. Academic research in this area suggest that AI causes a host of dysfunctional sexual and reproductive behaviors in cattle. (Mohanty of the National Dairy Research Institute, 2018), (Diederich et al. 2012).

  • Vitrification Effects of oocyte vitrification on histone modifications (Yan et al 2010). 

  • Cryopresevation "Studies have also shown that epigenetic alterations are associated with vitrification, a technique of instant cryopreservation of oocytes or embryos. Wang et al. 2010)

  • Superovulation, also known as controlled ovarian hyper stimulation. influenced by fertilization, and superovulation clearly disrupted H19 gene expression in individual blastocysts Fauque P, Jouannet P, Lesaffre C BMC Dev Biol, 2007). Both maternal and paternal H19 methylation were perturbed by superovulation, in a dose-dependent manner, with changes in imprinted methylation more frequent at higher hormone dosages  Market-Velker BA, Zhang L, Magri LS, Bonvissuto AC, Mann MR Hum Mol Genet, 2010

  • Preservatives and Mediums. It has been shown that gene expression and methylation were adversely affected by the culture medium used in ART for ET (Doherty et al. 2000). Also, extenders used to preserve the collected semen basically consist of a buffered solution that contains a cryoprotectant (eg. antifreeze compounds and antifreeze proteins) and antibiotics. Many variations have been tried in the basic recipe for semen extender. “The agricultural industry has found that the optimal extender for a given species seems to be very species-specific and that is turning out to be true with wild animals also. Perhaps some clues for safe semen preservation can be found in the natural world from studying certain female reptiles who have the potential for keeping sperm viable within their bodies for up to 6 years after mating.” (Cherfas, 1984).

  • Heterzygosity: “Artificial insemination was really beginning to take off in the 1960s…Today, three-quarters of Holsteins result from artificial insemination. Even those born from a 'natural mating' usually have a grandfather that was an artificial insemination bull. The widespread use of artificial insemination is what allowed these two bulls to have such a large impact.” (Dechow, C, 2017). After AI was implemented, COI was seen to double every 20 years. Between 1884 to 1928 the average COI was 3.4% (percent of genes in common between any two animals). By 1990, the consistent use of AI had resulted in Holstein inbreeding rates doubling (COI >6.5%). This indicates the effects of AI selection for more productive, functional cattle - and reflects a narrowing of the genetic base. In 2011, the vast majority (>95) of the Holstein Population was significantly inbred (COI 12.8%). “As expected, the percentage of inbred animals was high (>95%) for HF, and bulls’ inbreeding in all the collections mirrors the level of the in situ populations. Among cryobanks, the US collection had the highest percentage of highly inbred animals (20.1%)… In that collection, very highly inbred animals, such as Aggravation Cavalier Image-Red (26.1%), and Betsey Golden-Genes Bolero-ET (25.2%), were found to be present.” (Danchin-Burge, C., 2011). 

  • Proliferation of Lethal Recessives. Unknown and deleterious recessive traits can be spread through AI. “Among cryobanks, the US collection had the highest percentage of highly inbred animals (20.1%)” and the 2 bulls’ semen used by cryogenics labs. One in particular “…carried two lethal genetic recessives.” said Liu, a leading authority on bovine Y-chromosome variations. 

  • AI Transmitted Genetic Disorders are Impacting Fertility. Betsey Golden-Genes Bolero-ET is just one of the Haplotypes impacting fertility according to the Holstein Association USA, Inc., 2016).

  • Reflexive Ovulation. It could be argued and there is evidence that yak are in-part reflexive ovulaters (expression of estrus is altered by presence of bulls - not steer), making them poor candidates for AI. There are several reports on the estrous behavior and the primary factors causing differences is the footing conditions and the number of other herdmates in proestrus or estrus at the same time. 
  • Critical Periods: The following quote from Smith et al. (2015) hits on some additional issues that I believe are very important for you to consider. Let me translate first: When we are talking about the “critical periods” for epigenetic problems to occur, these authors believe the big ones are: 1) while the sperm and egg cells are being made, prior to fertilization and 2) immediately at and after fertilization. Disruption or insult during these times allow inappropriate information to be passed on to offspring. Similarly, there is a good body of research indicating that many species (particularly reflexive ovulators, monogamous species, and those with extended precopulatory mating rituals - like yak) are dependent on mating activities for normal, healthy development to occur. In yak, the bull is generating new sperm (spermatogenisis) while he is tending, during her estrous cycle (prior to and after ovulation) she is undergoing egg development (oogenesis). What occurs to them both during this critical period changes the gene expression (through DNA methylation, histone modification, endocrinological alterations, etc) activating and deactivating appropriate sites in the genome, making the offspring “tuned” to the environment in which it will be born (pretty cool huh??). Mess with the programing at this time and you get problems. 

    They say: “epigenetic stability is reprogrammed globally in two phases of the life cycle: in primordial germ cells (PGC) during gametogenesis and then in the zygote immediately after fertilization. The widespread epigenetic reprogramming in PGCs is associated with a global demethylation and is thought to be important for preventing the transmission of inappropriate epigenetic information to the next generation. Although zygotic demethylation seems to occur globally, some genomic sequences, including imprinted genes, maintain methylation during preimplantation and are essential for proper development.” Smith et al (2015) Epigenetic consequences of artificial reproductive technologies to the bovine imprinted genes SNRPN, H19/IGF2, and IGF2R Frontiers in Genetics 6:68

RISKS TO BREED-INTEGRITY BY ARTIFICIAL INSEMINATION

AI Regulation Necessary to Protect the Integrity of the Registry (eg. Holsteins).

There are several potential consequences of AI that could impact breed integrity in the NAY. It could be argued that these problems are common to all poorly regulated breed associations. However, the history of the Holstein illustrates all of these problems in one story from a single association.

 

  • ART Decimated U.S. Heritage Breeds. “As the last of the nation's heritage cows disappear, it might be the dairy industry that suffers most…Over the past century, the rise of the Holstein cow has decimated many native and heritage breeds. Fewer than 4,000 Guernsey cattle were registered last year, down from the 44,000 tallied in a 1930 U.S. Department of Agriculture report. The 6,000 Red Poll cows accounted for in the 1920s have dropped to just 524, and only 245 registered Milking Shorthorns remain today, falling from several thousand as recently as the 1970s” (Kral, L, 2017). Mega-farm and big businesses were conferred an advantage by the use of AI, with disadvantage disproportionately impacting the small farms, driving many out of business.
  • AI Holstein-Crosses Negatively Impacted British Heritage Breeds.“Most of those black-and-white cows munching grass out in the fields are, we fondly assume, traditional, familiar Fresians. We assume incorrectly. Thanks to the recent change of policy, Fresians are being replaced all over the country, with astonishing speed, by Holsteins, a breed that originally came from Denmark but which has been refined to a high pitch of productivity by American farmers. This transformation has been made possible by imported bull semen” (Cathhart, 1996).

Statistics on NAY Health. 

We Don't Need ART  - Best-Practices in Line-breeding. Continued and careful breeding is a viable alternative. UC Davis is not unique and teaches “inbreeding can be a useful tool for plant and animal breeders who want to impart particular advantageous homozygous traits into their crops or livestock. When inbreeding, breeders should identify and eliminate from further breeding individuals displaying deleterious traits” (UC Davis, 2018).

SUMMARY

"The time has come for ethics to be removed from the hands of the philosophers and biologisized.Look closely at nature. Every species is a masterpiece, exquisitely adapted to the particular environment in which it has survived. Who are we to destroy or even diminish biodiversity?"

 - E.O. Wilson, Sociobiology

Recommendations for AI Regulation.

 

As we have seen, epimutations and associated health risks become inevitable with the use of ART. Given the multiple known risks: epimutations, negative health consequences, anticipated and known economic consequences, and risks to Breed Integrity of ART - it is recommended that IYAK adopt an informed and ethical ART policy.

An informed and ethical policy would be one that achieved these Goals:

  1. Supports Private-Property Rights and Allows Open Competition
  2. Requires Best Practices seen in other professional breed associations. Some of these ethical and health issues can be mitigated by the regulation of the semen collection and insemination process by professionals. These are the Industry Standard for many professional breed associations. 
    •  enetics Centers
    • Certified Technicians
  3. Provides a valuable registration alternative for ART offspring.

Benefits: These measures would go far in achieving these goals without compromising the Integrity of the Foundation Registry.

  1. Accurate Education of Association Members: On the Best-Practices of Line breeding, as well as the cost-benefit analysis of AI.
  2. Economic Stability. Stabilize economic impact and well-being of the NAY breed, particularly to small breeders (ave. 10 animals) who cant afford market devaluations.
  3. Improve Genetic Diversity. For the purposes of importing novel semen from (and to) geographically isolated ex-situ herds. 
  4. Overcoming Geographic Limitations. Decreased Quarantine Risk and Expense can offset Out-of-country importation of AI sperm. 
  5. Lack of Favoritism to Large Players, equal supporting the needs of Small Yakers. You can decide you don't care if there is the consequences aren't of importance to you or NAY. But you can’t do the right thing and keep ART technophiles happy. It is misinformation, delusion and lies that ART is harmless.