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Personal Genomics...

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Study Guide for Personal Genomics Lecture by Dr. Wynn Meyer on 11/18/19

1. Draw your genome activity. Note that there are 23 sets of chromosomes: 22 pairs of autosomes and 2 sex chromosomes. What parts of the genome contribute to specific types of diseases, for example? If things were simple, then particular diseases would map to one particular part of the genome and we would be able to then sequence that region. BUT traits are very complex. 2. What is a gene? ● Defined for this talk as one or more exons (and introns) that can be transcribed into RNA and translated into protein. (NOTE that this definition does not account for all genes in the genome – some genes do not encode proteins because the RNAs are not translated into protein). ● Genes are RARE! How do we link phenotypes within the genetic variants that underlie them? ● In order to impact a phenotype, a variant would have to influence a gene. You have heard about SNPs before. What are they? ● SNP stands for Single Nucleotide Polymorphism. It means some people will have one base at a certain position in a sequence of bases, and other people will have a different base at that position. The two forms of SNP are called alleles. ● The term allele can refer either to the nucleotide at the SNP (A/G or T/A) or to the combination across both SNPs (AT/GA). ● Either way, it represents one ‘version’ of the sequence. ● The combination of alleles that a person has at a SNP is called a genotype. Mutation generates variation in sequence.

3. In order to im-

pact a phenotype, a variant (such as a SNP) would have to influence a gene. ● There are 25,000 genes in the human genome (so genes are rare). There are ~3 billion nucleotides in the haploid genome. ● Most genetic variants do not do anything (because of the frequency of genes in the genome). ● Likely ~1 in 300 SNPs could affect a gene. What is genetic drift? ● This process leads to changes in the makeup of alleles in a population. ● Genetic drift is the variation in the relative frequency of different genotypes in a small population, owing to the chance of disappearance of particular genes as individuals die or do not reproduce. Most human genetic variants are present in multiple populations. What are “private” SNPs? Why are “private” SNPs so rare? ● SNPs discovered from sequencing the whole genome of 2,504 humans from 26 different populations. ● “Private” SNPs are fixed in only one population sample but absent in others, which is why they are considered private. ● “Private” SNPs are so rare because human migrations are very recent. ● Human populations experience frequent gene flow. ● To identify differences between populations, we can genotype using a SNP chip (microarray).

To predict what contributes to a particular phenotype, we expect to look for differences in genotypes (through different SNPs). Some variants can help us trace our history. Scientists take many SNPs to determine what the

likelihood of history would be. ● Different SNPs will be more or less useful in determining whether an individual’s ancestors came from Kenya or from Greenland. ● Where are these SNPs located in the genome? The regions that can help you figure out where your ancestors lived!

In trying to associate genetic variation with phenotypic variation, we can ask informally – does it run in families? ● A more formal analysis can be determined by determining the proportion of variance due to genetic contributions using the equation: h2 = VG/VG + VE =VG/VP ● Note that you are not responsible for this equation but you should know that both genetic (G) and environmental (E) factors contribute to variance (V). Are traits simple or complex? EXAMPLES: ● Eye color is a SIMPLE trait. Eye color can be predicted with ~90% accuracy from the genotype at 1 site. ● Skin color, on the other hand, is a COMPLEX trait. Many regions of the genome are responsible for determining skin color.

4. How have we identified genes associated with phenotypes? ● Try to isolate a single gene that is inherited with a phenotype… ○ In model organisms, we can induce mutations and use controlled breeding. ○ In human families, we can follow simple phenotypes.

What is the significance of recombination that occurs during meiosis? ● Recombination is a process by which pieces of DNA are broken and recombined to produce new combinations of alleles. This recombination process creates genetic diversity at the level of genes that reflects differences in the DNA sequence of different organisms.

Genome Wide Association Studies (GWAS): Many genomes sequenced and SNPs determined. This approach is used in genetic research to associate specific genetic variations with particular diseases. The method involves scanning the genomes from many different people and looking for genetic markers that can be used to predict the presence of disease. ● Cases = People with the phenotype of interest. ● Controls = People without the phenotype of interest. ● Then look for the frequency of SNP with the phenotype. Frequency SNPs that are near each other in the genome show similar association patterns… ● Then find SNPs associated with particular phenotypes.

A research wants to determine the genetic basis of speaking French, so she collects samples from 500 French people and 500 people from elsewhere in Europe and genotypes them at 100,000 SNPs. She analyzes the data to find SNPs that have different allele frequencies... What have we learned from GWAS? ● Genome-Wide Association Studies have helped us to understand the links between genetic variants and phenotypes. These studies have to be corrected for population structure and can sometimes find different associations in different populations. ● Has been very successful in identifying novel variant-trait associations. Note that different human populations are not represented equally in GWAS. Why might this be a problem? ● GWA studies have been centered in populations of European descent, and the degree to which knowledge gained from these studies is transferable to other populations has not been extensively investigated.

● Recent reports such populations as Chinese, Japanese, Koreans, and Pacific islanders represent some of the first in a new wave of GWA studies in non-European populations, as researchers seek to search additional groups for new findings on: ○ Widely distributed phenotypes. ○ To consider new phenotypes that are more prevalent in non-Europena populations. ○ To establish the generality of findings obtained initially in European and European Americans.

What we’ve learned so far… ● Genetic variants arise by mutation and spread through populations by drift. This creates SNPs (variants within populations) that vary in allele frequency between populations. ● Combinations of SNPs can be used to infer ancestry because of these allele frequency differences. ● Phenotypes can be non-heritable (usually caused by the environment), simple (mostly predicted by variation at one gene, or complex (determined by multiple genes).

5. What are some caveats of the genomic tests that are commercially available for personal genomics? ● A few direct-to-consumer (DTC) genomics companies: ○ 23andMe, African Ancestry, Ancestry.com, Helix ● These companies have consumers spit in a vile and they promise that in turn you will: ○ “Understand the past, present, and future of your family’s health... “ ○ “Genetic insights into your ancestry, traits and health so you can learn more about your past and make more informed decisions about your future…” ● What’s really going on? The accuracy and informativeness of any test depends upon the panel of SNPs used to infer ancestry and disease risk.

What DTC genomic testing can and cannot tell us: ● We can learn… ○ Proportions of ancestry from populations well representing in the companies databases. ○ Risk for diseases that are highly heritable and have strong genetic associations (in the populations well represented in the companies’ databases as well…) ● We cannot learn… ○ Proportions of ancestry from other populations (may be mistakenly assigned to known populations).

○ Risk for disease that do not have clear associations or have not been studied in the relevant populations. ○ Our identity!...