Genomes

Genomics

The study of whole genomes

• genomics involves the development and application of more effective mapping, sequencing and computational tools

• used to predict existences and functions of previously undefined genes

  • verify predictions using molecular biology techniques

• sequencing the (human) genome reveals the blueprint for our form and functions

Human Genome Project

• first formally discussed in 1985

• discovery science: identification of all elements in a biological system

• officially began in 1990, estimated 15 years, $3 billion

• 3-5% of budget committed to studying the ethical, legal, and social implications (ELSI) of human genome mapping. Social and personal repercussions are generating new areas of biolocial concern

• 2001: draft version of human genome published

• 2003: “completion” of project, covered 92% of genome

  • remaining 8% contains highly repetitive DNA, hard to read and to place into order

• 2022: complete human genome sequence published by the Telomere-to-Telomere (T2T) Consortium

  • used newer sequencing technologies that are capably of long sequence reads (able to sequence large stretches of repetitive DNA)

Recall: Two approaches to using genetics to study development

• genome sequencing projects and the universality of biological processes lend themselves to reverse genetics

• GWAS (genome-wide association studies) can be used to identify genes of interest (forward genetics)

GWAS

• large-scale approach to identifying genes and gene variants of interest

• thousands of SNVs (single nucleotide variants) analyzed across the genomes of many individuals to identify possible genotype/phenotype associations

• analysis done thru whole genome sequencing (WGS) or genome-wide SNP arrays

• association confirmed thru more conventional studies

Benefits of GWAS

• identification of thousands of novel variant/trait associations (as of 2019, there are 52416 such associations)

• identifcation of risk loci for a broad range of medical issues

• can identify novel genes of unknown function, or identiy a previously unknown role of a gene is disease pathology

• can used identified associations to screen people who are at risk of developing certain diseases

• can identify new target genes for drug development

Benefits of GWAS Figure

Limitations of GWAS

• There are ethnic differences in risk variants–was the study sufficiently broad to capture these?

• Much of this work have been done on populations of European origin – other populations are underrepresented.

• genetic variants can only explain a small fraction of the heritability of a disease trait– it misses environmental factors

• Difficulty in analysis e.g. Which SNV actually maps to a gene that causes the trait, and which are merely linked to the gene? Which SNVs are in noncoding sequences?

• Cannot identify all genes responsible for complex traits. Likewise, has limited predictive value

Limitations of GWAS Figure

Example of GWAS Limitation

Mis-diagnosis of hypertrophic cardiomyopathy due to mismatched reference pool

Mis-diagnosis of hypertrophic cardiomyopathy due to mismatched reference pool

• the Human Genome Mutation Database is a database with human mutations that have been associated with disease. It is based on data from published studies.

  • a number of allelic variants identified in this database were associated with hypertrophic cardiomyopathy

• these genetic variants originally identified because they appeared more frequently in tested patients than in unrelated control populations

  • TNNT2, variant K247R: gene studied in Spain

  • TNNI3, variant P82S, gene studied in U.S

  • MYBPC3, variant G278E: gene studied in France

• mainly based on European individuals, but these allelic variants have been used for genetic tests that screen for disease

How prevalent are these disease-associated allelic variants?

• Manrai et al., (2016) used 3 other databases to check the allelic frequencies of these variants in the greater population (note the diversity)

  • NHLBI Exome sequencing project (4300 White Amer. + 2203 Black Amer.)

  • 1000 Genomes Project (phase 1: 1092 individuals across 14 populations worldwide)

  • human genome diversity project (938 individuals across 51 populations worldwide)

• Manrai et al. also looked at clinical records of patients w/ hypertrophic cardiomyopathy, including info about which allelic variants they have

How prevalent are these disease-associated allelic variants? Figure

Consequence of a mismatched reference pool

• Misdiagnosis of hypertrophic cardiomyopathy

• these 5 allelic variants had previously been identified to be associated with hypertrophic cardiomyopathy.

• While these variants are rare in White Americans (ie. European ethnicity), they are more frequent in Black Americans (ie. African ethnicity).

• Mis-classified as disease-causing variants, leading to misdiagnoses of Black Americans

Allelic Variants of African-American Genomes

• African-American genomes contain more “private sites” i.e allelic variants that are only present in one population but not the other

Genome Projects Targeting Other Populations

• Human Heredity and Health in Africa (H3Africa): “H3Africa empower African researchers to be competitive in genomic sciences, establishes and nurtures effective collaborations among African researchers on the African continent, and generates unique data that could be used to improve both African and global health”

• GenomeAsia 100k: “GenomeAsia 100K plans to create reference genomes for Asian population as well as identify rare and frequent alleles associated with these populations”

• SIlent Genomes Project: genome project targeting Indigenous populations in Canada

Concerns about Commercial DNA Tests

• what did you gain?

• who own the data after you have submitted your biological sample?

• how else might that data be used? how has it already been used? did you anticipate that application or consent to it? was your consent properly informed

“DNA on loan”

• Tri-council policy on human research includes provisions for working with genetic material and creation of biobanks

• this contains specific policies on working with Indigenous populations, b/c of past abuses of such research:

  • DAN samples remain the property of the individual. The researcher has only the permission to work with these samples for a specific purpose

  • if a new research objective can be carried out, consent must be given again for this new use

Social and Ethical Concerns of Genomic Research

• which populations are represented in the Human Genome sequence? Who decides which population is the normal reference group?

• Who decides what questions get asked, or what diseases get studied?

• who owns the genetic data? who benefits

• what impact does this have when genomic studies are carried out?

• importance of diversity and representation in research subjects, researchers and those who fund the research and make the policy decisions

• importance of treating research subjects and their genetic data with resect