Biol 4355 - Genética Humana Capítulo 7 – Rasgos Multifactoriales UPR – Aguadilla JA Cardé, PhD

1. Biol 4355 - Genética Humana Capítulo 7 – Rasgos Multifactoriales UPR – Aguadilla JA Cardé, PhD

2. Objetives • To consider characteristics that represent input from many genes (multifactorial) • To review the tools used to study multifactorial traits

3. Genes, Environment and Traits Few, if any, genes act alone Environmental factors and other genes may modify expression Traits can be described as - Mendelian = Caused by a single gene - Polygenic = Caused by multiple genes Both can be multifactorial or complex due to an interaction between genes and the environment (epigenesis)

4. Genes, Environment and Traits Single-gene traits are discrete or qualitative - Often produce an “all-or-none” effect Polygenic traits produce a continuously varying phenotype - Also called quantitative traits - DNA sequences involved are termed quantitative trait loci (QTLs)

5. Genes, Environment and Traits Figure 7.1

6. Polygenic Traits Are influenced by interaction of genes and by the environment Examples: - Height - Skin color - Body weight - Fingerprint patterns - Behavioral traits

7. Polygenic Traits Individual genes follow Mendel’s laws, but their expression is hard to predict Effect of genes is additive or synergistic - However, input of genes is not necessarily identical The frequency of distribution of phenotypes forms a bell-shaped curve!

8. Fingerprint Patterns Dermatoglyphics is the study of fingerprints The number of ridges is largely determined by genes and prenatal contact with the amniotic sac The average total ridge count is 145 in a male and 126 in a female Abnormal numbers in Down Syndrome

9. Fingerprint Patterns Figure 7.2

10. Height The difference in height between the two sets of students is attributed to improved diet and better overall health - 1920 height max = 5’9” - 1997 height max = 6’5” Genome-wide association studies have identified dozens of genes that affect height - Also, certain SNPs patterns are seen in individuals with periods of rapid height increase

11. Height 1920 height max = 5’9” 1920 height max = 6’5” Figure 7.3

12. Skin Color Melanin protects against DNA damage from UV radiation Exposure to the sun increases melanin synthesis All have same number of melanocytes per unit area of skin - However, we differ in melanosome number, size and density distribution

13. Skin Color Figure 7.4 – Modelo de 3 genes con dos alelos cada uno, para color de piel . Se sortean de multiples formas dando mutiples tonos de color. (Gemelas, padre aleman madre jamaiquina)

14. Skin Color The definition of race based largely on skin color is a social construct more than a biological concept Skin color is NOT a reliable indicator of ancestry - Overall, 93% of varying inherited traits are no more common in people of one skin color than any other

15. Summary Polygenic Traits - Determined by more than one gen and vary continuously in expression Multifactorial Traits - Determined by a combination of a gene, or genes and the environment - A bell curve describes the distribution of phenotypic classes of a polygenic trait.

16. Investigating Multifactorial Traits Empiric risk - measures or predict the likelihood that a trait will recur based on incidence in specific population - ethnic group, community, families with CF Incidence- the rate at which a certain new event occurs in a population during some period of time Prevalence - number of individuals who have a particular trait at a specific time (ie. during a year)

17. Empiric Risk Is not a calculation It is a population statistic based in observations It will increase with: - the severity of the disorder - the number of affected individuals in a family - how close (consanguinity) is the individual to the affected individual Ex: cleft lip

18. Investigating Multifactorial Traits Cleft lip is more likely in a person who has a relative with the condition The closer the relationship between two individuals, one of them having the condition, the greater the probability that the second individual has the trait. They share more genes. Figure 7.5

19. Investigating Multifactorial Traits Table 7.2

20. Heritability (H) Estimates the proportion of the phenotypic variation in a population due to genetic differences What factors contribute to the observed variation in a trait? Figure 7.6

21. Heritability (H) • H=1:variability completely due to gene action (lab rats) • No environmental variability: genetic differences alone determine expression of a trait • H changes as environment changes. • Winter months vs Summer months

22. University of Puerto Rico Intercampus Doctoral Program in Biology Effects of Plasticizers on Vtg Synthtesis BPA (μg) 250 375 500 1000 C+ Vtg 169 153 116 Alb Anti S1 (Vtg) 1 2 3 4 5 6

23. University of Puerto Rico Intercampus Doctoral Program in Biology Effect of Methoxychlor on Vtg Synthesis Mtx 70 μg C- C+ Vtg 169 153 116 Alb Anti S1 (Vtg) 1 2 3 4 5 6 7 8 9

24. University of Puerto Rico Intercampus Doctoral Program in Biology Dose Response Experiments (a) Dead animals.

25. Heritability (H) Researchers use several statistical methods to estimate heritability One way is to compare the proportion of people sharing a trait to the proportion predicted to share the trait The expected proportion is derived by knowing the blood relationships of the individuals and using the C of R

26. Coefficients of Relatedness The proportion of genes shared between two people related in a certain way Table 7.4

27. Adopted Individuals Similarities between adopted people and adopted parents reflect mostly environmentalinfluences Similarities between adoptees and their biological parents reflect mostly genetic influences Therefore, information on both sets of parents can reveal how heredity and the environment both contribute to a trait

28. Twins Twin studies have largely replaced adoption methods Concordance measures the frequency of expression of a trait in both members of monozygotic (MZ) or dizygotic (DZ) twins - Twins who differ in a trait are said to be discordant for it For a trait largely determined by genes, concordance is higher for MZ than DZ twins

29. Twins Table 7.4 Tuberculosis?? Vs Susceptibilidad

30. Separating Genetic and Environmental Influences Dizygotic twins = Shared environment and 50% of genes Monozygotic twins = Identical genotype and shared environment Twins raised apart = Shared genotype but not environment Adopted individuals = Shared environment but not genes

31. Twins Figure 7.8

32. Genome-Wide Association Studies Older techniques search for known gene variants, typically in only a few people Sequencing of the human genome and the HapMap project (which identifies SNPs) have led to a new tool Genome-wide association studies seek correlations between SNP patterns and phenotypes in large groups of individuals

33. Genome-wide Association Studies (GWAS) Studies to identify common variants behind a particular phenotype Study to identify genetic associations with observables traits (Blood pressure/weight) Genetic markers: used to follow variations, across the genome, form patterns compared between groups with a disease

34. underexpressed Table 7.5

35. SNPs SNPs (single nucleotide polymorphisms) are sites in a genome where the DNA base varies in at least 1% of the population In these studies, SNPs span the genome, rather than define a single gene - A SNP can be anywhere among our roughly 3.2 billion base pairs

36. SNPs Figure 7.9

37. Genome-wide association studies seek SNPs that are shared with much greater frequency among individuals with the same trait than among others Figure 7.10

38. A Step-wise Approach to Gene Discovery Figure 7.11

39. Study Designs In a cohort study, researchers follow a large group of individuals over time and measure many aspects of their health In a case-control study, pairs of individuals from different groups are matched so that they share as many demographics characteristics as possible - SNP differences are then associated with the presence or absence of the disorder

40. Study Designs The“affected sibling pair” strategy scans genomes of siblings for SNPs shared by those with the condition, but not by those who don’t have it Homozygosity mapping is performed on families that are consaguineous - The children in this case are more likely to inherit two copies of the mutation

41. Limitations of Genome-Wide Association Studies 1) They include so many data points and so are prone to error 2) They reveal associations between two types of information, not causes 3) Bias can be introduced in the way the patient population is selected 4) Their accuracy is affected by complicating factors, such as phenocopy and epistasis 5) They may miss extremely rare SNPs

42. Table 7.6

43. Asignado: Body Weight Body weight is a multifactorial trait that reflects energy balance About 30% of all adults in the US are obese, and another 35% are overweight Scientific studies use a measurement called body mass index (BMI) = weight (kg)/height2 (m2)

44. Body Mass Index (BMI) Figure 7.12

45. Body Weight Studies on adopted individuals and twins indicate a heritability of 75% for obesity Lifestyle, including diet and exercise, are environmental components impacting weight Genes influence hunger and metabolism

46. Leptin and Associated Proteins Leptin is a protein hormone produced by fat cells - Acts on the brain to decrease appetite Ghrelin is a peptide hormone produced in the stomach - Responds to hunger by increasing appetite These and other hormones are important for general weight regulation

47. Leptin and Associated Proteins Table 7.8