Key Terms: 10_Modern Genetics

Genome Wide Association Studies (GWAS) (Primary)

Trait/phenotype mapping method. Relies on SNPs and on linkage. Used to locate genes or regions associated with traits.

Chromatin Modifications (Mapping Context)

Listed alongside GWAS in trait mapping. Associated regions can affect regulation and expression, not only coding sequence.

Gene Editing / CRISPR

"Clustered Regularly Interspaced Short Palindromic Repeats." Technology for editing genes.

Genes Are on Chromosomes

Each gene has a locus on a chromosome.

Alleles on Homologous Chromosomes

The two alleles of a gene sit at the same locus on the two homologs (example

Independent Sorting

Genes on different chromosomes (different homologous pairs) sort independently during gamete formation.

Genes on the Same Chromosome

Do not always stay together because recombination can separate them.

Sister Chromatids

After replication, each chromosome is two identical copies joined together.

Recombination (Crossing Over) (Primary)

One sister chromatid exchanges genetic material with the homologous chromosome. Allows genes to be mixed and matched even when on the same chromosome.

Recombination (Secondary)

Occurs between non-sister chromatids of paternal and maternal homologs. The crossover point is the chiasma. Products are recombinant chromatids.

Non-Sister Chromatids

Chromatids belonging to different homologs. The chromatids that exchange material in crossing over.

Chiasma

Visible crossover point between homologous chromosomes.

Recombinant Chromatids

Chromatids carrying a new combination of alleles after crossing over.

Homologous Recombination (Repair)

Repair mechanism for double-stranded breaks using a matching template to fix broken DNA. Came first in evolution, then was co-opted for sexual reproduction (meiotic crossing over).

Recombination Frequency

Recombination is not equally likely between all genes on a chromosome. Closer genes are less likely to be separated.

Linkage (Primary)

Genes that are close together are less likely to sort independently.

Linkage (Secondary)

Useful for locating genes by finding traits that tend to be inherited together.

Pedigree (Family Tree)

Used to look at inheritance patterns (dominant, epistatic, and so on).

Linkage Mapping

Alleles likely to show recombination are far apart (not inherited together). Alleles unlikely to show recombination are close (stay linked and inherited together).

GWAS Method (Secondary)

Use SNPs to try to locate genes. Some people in the population carry a SNP at a given location. If the SNP is near (linked to) a causative gene, it appears more often in affected individuals.

GWAS Statistics

The odds of a SNP associated with disease are calculated. Statistical evidence indicates a chromosomal region (for example, chromosome 3) contains a gene of interest.

GWAS Sample Size

Trait-associated gene discovery increases with sample size, so very large datasets are needed.

Candidate Gene Approach

Testing individual genes based on theoretical guesses. Produced non-replicable claims for schizophrenia.

Locus (GWAS Output)

Region of the chromosome identified as important for follow-up.

Gene vs. Regulatory Region

A GWAS hit may point to a regulatory region rather than a protein-coding gene.

NHGRI-EBI GWAS Catalog

Public catalog of human GWAS results (the "power of GWAS").

Limitations of GWAS

Depend on large, diverse, openly accessible datasets. Still far from this reality 20 years after "the" human genome.

CRISPR/Cas9 (Primary)

Guide RNA matches a genomic sequence and directs the Cas9 protein to cut the DNA (double-stranded break) at the matching site.

Guide RNA

RNA that pairs with the matching genomic sequence and directs Cas9 to its target.

Cas9

Protein (nuclease) that cuts both strands of DNA at the site chosen by the guide RNA.

"Useless Knowledge" (Basic Science)

CRISPR originated in bacteria, which gain resistance to foreign DNA by saving some of it and using it to scan for that sequence later.

CRISPR Timeline

Developed as a technology in 2012, excitement in 2015, NIH initiative in 2018, FDA approval in 2023.

Casgevy

First approved CRISPR therapy. Could potentially treat tens of thousands of people with one of two blood disorders.

Personalized Gene Editing (KJ's Therapy)

A CRISPR therapy designed to work only for one patient (KJ), in contrast to earlier therapies designed to treat many people.