Genetics and Genetic Abnormalities

1. Genetics and Genetic Abnormalities CearaFjeld

2. Overview • Review of Gamete formation, fertilization, and the central dogma • Improving genetic performance through crossbreeding due to heterosis and selection • Genetic abnormalities • History • Detection/ testing for genetic disorders • Genome manipulation • Transgenics • Gene modification

3. Meiosis • 2 meiosis divisions to produce gametes • Independent assortment and crossing over allow genetic mixing and recombination of genetic material (Students know…)

4. Fertilization • Quality gametes needed for fertilization and for the embryo to be a viable pregnancy • Chemoattractant attracts sperm towards egg • Sperm migrates through follicle cells and bind to the zonapellucida • Acrosome reaction exposes hydrolytic enzymes to help sperm go through the zonapellucida • Zonapellucida’s 3 glycoproteins normally acts as a barrier to fertilization across species • Mechanisms that ensure only one sperm fertilizes the egg: • Rapid depolarization of the egg plasma membrane • Egg cortical reaction (Wilson and Hunt, 2002)

5. DNA Transcription mRNA Translation Protein

6. Genetic Performance: Crossbreeding Programs • Breed complementary • Favorable genes from a different breed because such genes are absent or at low frequency in the initial breed • Hybrid vigor • Enhanced performance of crossbred animals due to heterosis • Increases heterozygosity • Eliminates the chance of inbreeding depression • Genes act in a nonadditive manner

7. Study Evaluating offspring of F1 Jersey x Holstein sires with Holstein dams (Maltecca et al., 2006) • Included primiparous and multiparous dams • Conception rates- no change • Perinatal mortality and preweaning mortalities higher for purebred sires • Males higher perinatal mortality compared to females • Birth rates and dystocia rates less for F1 cross offspring • Total serum protein and serum IgG higher in the crossbred calves • Related to increased calf performance • No difference in multiparous/primiparous or male/female calves • Fecal consistency scores in calves from birth to 7 days old were lower in crossbred sires

8. Study evaluating calving difficulty and stillbirths between purebred and crossbred • Crossbred sires and purebred Holstein dams studied as well as purebred Holstein sires and crossbred dams • Calving difficulty and stillborns were reduced when using crosses for the dam or sire • (Heins et al., 2006)

9. (Heins et al., 2006)

10. Study on Beef cattle calving rate and calf survival • (Guerra et al., 2006) • Calving rate and calf survival increased when increasing the number of breeds in a rotation

11. (Guerra et al., 2006)

12. Genetic Abnormalities- History • Hippocrates first described in 460-375 B.C. • Up until middle ages, babies born with genetic abnormalities were allowed to perish • Religious beliefs helped protect children, yet deformed children were viewed as products of the devil • Mid-ninteenth century: interest and studies done on the causes of congenital abnormalities • Mendel’s paper, published in 1866, explained the principles of genetic transmission • Archibald Garrod first applied Mendel’s theories to the human disease, alcaptonuria in the early 1900s (Smith, 2002)

13. Prenatal screening • Determining prenatal screening depends on genetic condition to test, type of population tested, severity of the disorder, and the cost as well as sensitivity and specificity of the tests available • Results from testing may be beneficial to family members • Common for conditions such as phenylketonuria, hypothyroidism, sickle cell disease, and galactosemia • Screening methods have improved to detect specific alterations of a genetic disease • In 2002, 4 million newborns were screened that year in the U.S. • A genetic factor accounts for 20 percent of all congenital abnormalities (Smith, 2002)

14. Prenatal screening continued • Severe mental deficiency: I.Q. of 50 or below occurs in 4 in every 1,000 children and is 21.5-35 percent associated with genetic causes (Smith, 2002) • The cause and effect of the pathology of a disease isn’t just the result of a single gene, but is connections between genes, genotype, environmental factors, and genomic pattern (Kenner et al., 2005)

15. Prenatal screening tests • First trimester screening (nuchal translucency) • Blood test and ultrasound examination • Can help identify babies with Down Syndrome, Trisomy 18, or Trisomy 13 • Cystic Fibrosis Carrier Screening • Blood test used to tell women and men if they are carriers of cystic fibrosis • Modified Sequential Screening • Follow up test to the first trimester screening

16. Diagnostic tests • Abdominocentesis • First introduced in 1969 • Thin needle goes through the abdomen to remove a small sample of amniotic fluid • Tested for chromosome abnormalities and genetic birth defects • Chorionic Villus Sampling (CVS) • Obtains a sample of the chorion that surrounds the fetus • Done late in the first trimester • Provides chromosomes to diagnose chromosomal abnormalities, and genetic birth defects • Can be done earlier than abdominocentesis

17. Influenced by genetic screening: Congenital Hearing Loss, Usher syndrome • Mendelian disorder that is an autosomal recessive disease • Results in hearing impairment and often progressive retinitis pigmentosa • 0.05% to 0.1% of U.S. newborns have severe hearing loss, and more than half is caused by a genetic disorder • Genetic testing doesn’t cure disease, but has been proved to improve quality of life • Sensory input can be maximized • Hearing aids or cochlear implants • Improves speech development (Kenner et al., 2005)

18. Influenced by genetic screening: Sickle Cell Disease • Caused by amino acid substitution of valine for glutamic acid at the sixth position of the beta-globin gene in codon 6 on chromosome 11p15.5 • Mostly affects people of African, Mediterranean, Middle Eastern, and Indian decent • Not all affected equally by the disease • Mortality for children with the disease has decreased • Predicted from early genetic screenings, family education, and better medical care (Kenner et al., 2005)

19. Genetic manipulation through transgenics • Exogenous DNA inserted into an animal’s genome • Often used to investigate brain function and development • Often used to insert mutant human gene to create an animal model of the disease • Studies have shown symptoms of the inserted gene have not been consistent for all transgenic animals • In 2008, five monkeys successfully expressed the transgene for Huntington’s disease, yet they showed differences in disease presentation (Lois and Groves, 2012)

20. Methods of transgenics • Pronuclear injection • Injects exogeneous DNA into the nucleus of a zygote which then works its way in the host genome • One of the simplest methods • Viral-mediated transgenesis • Used when pronuclear injection is not practical or possible • Example: avian species, most large mammals • Uses lentiviruses because they are immune to developmental silencing

21. Genetic manipulation through gene modification • Random mutagenesis (forward genesis) • Expose an animal to a mutagen in order to induce changes in the DNA of the germ cells • Unbiased approach • Can identify genes not expected to contribute to the process • New method isn’t as costly as the original because the need for breeding schemes is eliminated • RNAi transgenesis • Inactivates a gene by disrupting expression at the level of its mRNA • Relatively inexpensive • Can be added into the gene using any of the gene-adding techniques

22. Genetic manipulation through gene modification • Targeted mutagenesis (reverse genetics) • Manipulation of a genome at a specific and predetermined location • Nuclear transfer • Permits targeted gene mutagenesis in animals where embryonic stem cells or primordial germ cells are not needed • Genes are targeted in fibroblasts • Thousands of colonies are screened in vitro to identify cells with appropriate targeting • Then nuclei is transferred into an oocyte • Zinc finger nucleases • Uses in vivo recombination • Eliminates the need to screen hundreds of animals for the appropriate recombination

23. References • Enkin, Murray, Marc Keirse, James Neilson, Caroline Crowther, LeliaDuley, Ellen Hodnett, and Justus Hofmeyr. "Screening for Congenital Anomalies." A Guide to Effective Care in Pregnancy and Childbirth. Oxford: Oxford UP, 2000. N. pag. Print. • Guerra, J. L., D. E. Franke, and D. C. Blouin. "Genetic Parameters for Calving Rate and Calf Survival from Linear, Threshold, and Logistic Models in a Multibreed Beef Cattle Population." Journal of Animal Science 84 (2006): 3197-203. Web. • Heins, B. J., L. B. Hansen, and A. J. Seykora. "Calving Difficulty and Stillbirths of Pure Holsteins versus Crossbreds of Holstein with Normande, Monteliarde, and Scandinavian Red." Journal of Dairy Science 89 (2006): 2805-810. Web. • Kenner, Carole, Agatha M. Gallo, and Kellie D. Bryant. "Promoting Children's Health Through Understanding of Genetics and Genomics." Journal of Nursing Scholarship 37.4 (2005): 308-14. 10 Nov. 2005. Web. • Lois, Carlos, and James O. Groves. "Genetics in Non-genetic Model Systems." Current Opinion in Neurobiology 22.1 (2012): 79-85. 24 Nov. 2012. Web. • Maltecca, C., H. Khatib, V. R. Schutzkus, P. C. Hoffman, and K. A. Weigel. "Changes in Conception Rate, Calving Performance, and Calf Health and Survival From the Use of Crossbred Jersey X Holstein Sires as Mates for Holstein Dams." Journal of Dairy Science 89 (2006): 2747-754. Web. • Smith, George F. "Historical Review and Recent Advances - Chapter 20- Congenital Abnormalities and Genetic Concepts in Neonatology." Neonatology on the Web. Mead Johnson Nutritional Division, 15 Sept. 2002. Web. 19 Apr. 2014. • "Students Know Heredity Is the Passage of Genetic Instructions from One Generation to the next Generation."Regional Professional Development Program. N.p., n.d. Web. Apr. 2013. • Wilson, John H., and Tim Hunt. "Fertilization." Molecular Biology of the Cell, 4th Edition: A Problems Approach. New York: Garland Science, 2002. N. pag. Print.