1040

Scans SNPs across the genome in many people to find variants correlated with a trait; points to regions where causal genes may lie. Shows association, not causation.

Single-nucleotide polymorphism: a one-letter DNA difference between people. Used in GWAS because SNPs are the most abundant variation and cheap/easy to genotype (chips read 500k to 5M).

Statistical correlation between alleles at different loci, usually because they sit close together and are rarely split by crossing over in meiosis.

Linkage disequilibrium: it is inherited together with a nearby causal variant, so it acts as a marker.

X = position in the genome by chromosome. Y = -log10(p), strength of association; higher = less likely due to chance. One dot = one SNP.

A SNP above the genome-wide significance line (p = 5 x 10^-8): a statistically significant association with the trait. Not proof of causation.

Compare allele frequency in affected (cases) vs. unaffected (controls). E.g., B allele 50% in cases vs. 20% in controls = associated.

How many times more likely you are to have a trait if you carry a variant. OR of 3 = 3x as likely. Common GWAS variants have OR near 1.

Correlation is not causation; hits may be LD neighbors of the real cause; misses rare alleles with large effects; results depend on sample size.

About 195,000 people; 50 new loci (e.g., OCA2/HERC2, TYR, IRF4). Shows GWAS on a physical trait.

The share of variation in a trait within a population explained by genetic differences. Says nothing about whether the trait can change.

The gap between high heritability from twin studies and the much lower variation explained by GWAS hits (e.g., height ~0.80 vs ~0.10).

GWAS fails to detect rare alleles and genes of very small effect. Likely true.

"Kind of has to be both": GWAS underestimates, AND twin studies overestimate (identical twins share environments more). Be skeptical of twin heritability.

Pedigree/twin design, GWAS hits only, and population design (genetic similarity among unrelated people).

~37,000 cases, ~113,000 controls; 108 loci, 83 new. Later (2022) study found 287 loci.

No single 'schizophrenia gene'; broad variation across nearly the whole genome contributes small effects.

Schizophrenia gene that sits under a GWAS peak AND carries rare protein-truncating mutations. Shows combining methods homes in on causal genes (synapse regulation).

Common variants have small effects; rare variants have large effects. Consistent with selection keeping harmful large-effect variants rare.

All treatments block the type 2 dopamine receptor; no new drug pathways in 50+ years. GWAS offers new targets.

~0.5 million genomes; ~5 significant loci; genetics explains 8-25% of variation; genes linked to olfaction and sex hormones; cannot predict an individual's sexuality.

"Genomes reveal some genetic basis for heterosexuality": the study could equally describe heterosexual behavior, avoiding a disease framing.

Built in a weekend from the Ganna study even though the study said genes cannot predict sexuality. Example of misuse of DTC genetic data.

A cottage industry (left-handedness, crime, risk-taking, fidelity, picky eating, God gene). Usually overstate tiny associations.

1.1 million people; 1,271 significant SNPs; explains ~12% of variation. Has a history of racial misuse.

IQ is genetic; IQ predicts success; so social programs are pointless; less-educated have more kids; variation falls along racial lines. Discredited pseudoscience revived in policy circles.

High heritability does NOT mean a trait can't change. Height is 80-90% heritable, yet Japanese boys grew 5+ inches in 50 years.

Rise in average IQ over time: US +18 points from 1948 to 2002. The Black-white gap is about half that historical change.

Adoption from a poor into a better-off family is linked to IQ gains of 12-18 points.

IQ is real and heritable, but there is no evidence that group IQ differences are genetic; US racial categories are a poor proxy for ancestry.

Lower among children raised in poverty, likely because poor environments keep genetic potential from being expressed.

The most important difference between the races is racism, rooted in slavery; you can oppose determinism without denying heritability.

Genetics explains differences WITHIN groups, not BETWEEN them; explicitly anti-racist; genetics doesn't excuse policymakers. Critics say the genetic basis is less clear.

The same genes can have different effects in different environments; reaction-norm lines can diverge or cross.

In a racist society, any genetic difference between dominant and minoritized groups will correlate with educational attainment and show up as a GWAS hit, reflecting environment, not ability.

Chimpanzees and bonobos. We share a recent common ancestor; we did not descend from chimps.

Humans originated in Africa; all non-African lineages branch from within African lineages (mtDNA). Left Africa ~55,000-75,000 years ago.

Migrants carried only a subset of African alleles (founder effect), so non-African diversity is a subset of African diversity.

DNA changes at roughly predictable rates, so sequence differences can date when lineages split.

Far more genetic variation within groups than between them; groups share nearly the same alleles. So human races are not genetically distinct.

Mating happened after humans left Africa, so Europeans and Asians carry more Neanderthal DNA (~1.5-2.1%) than Africans.

Led sequencing of the Neanderthal (2010) and Denisovan genomes from ancient DNA.

Archaic human lineage identified from DNA in a single finger/toe bone in Denisova Cave, Siberia. Contributed DNA to Asians and Oceanians (3-6% in Oceania).

~0.3%, introduced by humans migrating back into Africa (Chen et al. 2020).

Replaced by an H. sapiens Y chromosome after interbreeding (Petr et al. 2020).

Contribute to relevant variation: depression and psychiatric risk, severe COVID-19 risk, being a morning person.

Chromosome 3 haplotype inherited from Neanderthals raises risk of severe COVID; common in South Asia, rare in Africa (Zeberg & Paabo 2020).

Variant that helps Tibetans live at high altitude (low oxygen); inherited from Denisovans; rare in Han Chinese, rose to high frequency after Tibet was settled.

Human history is a mix of lineages (Neanderthal, Denisovan, unknown hominins), so racial purity is a myth.

Ancient DNA from Jefferson's hair confirmed he fathered Sally Hemings's children; raises privacy questions for living descendants.

Continuous trait tracking UV; genes include SLC24A5, MFSD12, HERC2/OCA2, DDB1. Alleles common outside Africa are also found inside Africa.

Keeping the ability to digest lactose (milk sugar) as an adult; most humans lose it after childhood.

Main European LP allele; regulatory variant in MCM6 controlling the nearby LCT (lactase) gene; rare in Africa.

Natural selection following the domestication of cattle (Neolithic Linear Pottery culture).

Different mutations near LCT arose separately in Europe and Africa (East African herders), so LP is not a 'European' trait.

They treat LP as proof Europeans are more evolved. Wrong: LP evolved repeatedly (often in Africa) and is only useful in dairy cultures.

Coded white nationalist term claiming science hides biological racial differences.

University of Chicago geneticist who warns colleagues about racist misuse of findings (uses the milk example in talks).

Improving the human race by selective breeding ("well born"); also framed as a social science to fix inequality. Intertwined with racism.

Coined 'eugenics'; invented regression and correlation; pioneered twin studies; estimated heritability of intelligence from pedigrees (1869).

Chicken breeder who founded the Eugenics Record Office at Cold Spring Harbor, NY (1910).

About 30 states passed laws; about 60,000 Americans sterilized; continued into the 1970s.

Restricted immigration from southern/eastern Europe and Asia on eugenic, racist grounds; not reversed until the 1960s.

US sterilization laws were used as models for Nazi laws (1933: ~400,000 sterilized), which escalated to euthanasia and the Holocaust.

Came from the Nazi doctors' trials; requires informed consent and subject welfare; basis of modern IRB oversight.

Reducing allele frequencies (especially rare ones) takes many generations; breeding exposes hidden alleles; a global multi-generation program is fantasy.

(1) Selecting some variants over others is discriminatory; (2) methods were forced. Gene editing may remove (2), so (1) must be confronted.

8-1 Supreme Court ruling that forced sterilization is constitutional; Holmes: "three generations of imbeciles are enough." Never overturned.

Charlottesville woman labeled 'feebleminded' after giving birth following rape; institutionalized and sterilized; her mother and baby daughter were also labeled.

Gave old racist views a modern scientific look; leaders like Alderman, Jordan, Lewis, Barringer promoted it.

UVA dean of medicine and national eugenics leader; worked with Davenport; pushed forced sterilization. Jordan Hall renamed Pinn Hall.

UVA biology chair/dean who supplied eugenic rationale and blocked faculty who disagreed. Mountain Lake lab renamed for Ruth Patrick.

Influential UVA president; ardent eugenicist who hired eugenicists and backed segregated schooling. Library renamed for Edgar Shannon.

Modernized UVA medicine; promoted hereditary racial differences and anti-miscegenation views. Wing renamed for Francis Collins.

Germline (egg, sperm, embryo) edits every cell and passes to future generations; somatic edits only treated tissue and is not inherited.

Repeated DNA in bacteria storing snippets of past viral (phage) DNA between spacers; part of a bacterial immune system.

Clustered Regularly Interspaced Short Palindromic Repeats.

1) Store viral DNA in the CRISPR locus; 2) transcribe and process into crRNA; 3) crRNA + Cas9 find and cut viral DNA.

Guide RNA base-pairs with the target DNA; Cas9 cuts both strands; the cell repairs, making a deletion or copying in a template.

Emmanuelle Charpentier and Jennifer Doudna (Chemistry).

Old way (construct into stem cells, select, inject, breed chimeras) was inefficient and imprecise; CRISPR is specific, simple, works in many species.

Off-target mutations, deletions, and mosaicism (only some cells edited).

It's easy and cheap: DIY kits (~\$179), biohackers injecting themselves.

It selectively perpetuates certain variants over others.

Announced the first gene-edited babies, twins Lulu and Nana (a third baby later); published no data; jailed 3 years; now back in the lab on DMD.

Receptor on white blood cells that some HIV strains use to enter T-cells; He Jiankui disabled it in the twins. Its other functions aren't fully understood.

No medical need (HIV transmission preventable otherwise); unknown risks; faked ethics approval; questionable informed consent; misled staff; secrecy; business interests.

Russian scientist who planned to edit embryos for inherited deafness; stopped after the WHO objected.

No country permits it (2020 study); US ban restored 2019; WHO recommends strict limits. In 2026 startups push to legalize therapeutic embryo editing.

Church: bans drive editing underground; parents, doctors, society decide. Collins: hubris; who decides what is an improvement?

Scientists set rules for recombinant DNA: containment, ban on cloning dangerous pathogens, public openness. Lesson: science should bring expertise into policy.

First FDA-approved CRISPR therapy (2023), for sickle cell disease; somatic (edits blood stem cells). Expanded to kids as young as 2 in 2026.

Engineer a patient's T-cells to recognize tumor surface proteins, then infuse them back to kill cancer. 9 FDA-approved therapies.

CRISPR delivered as mRNA + guide RNA by injection (like mRNA COVID vaccines) to edit liver cells for transthyretin disease; no cell removal needed.

More precise editors (CRISPR 2.0), targeted delivery (e.g., lungs for cystic fibrosis), fewer side-effect worries, MORE ethical debate about whether to edit.

The gray wolf. Domesticated ~15,000-40,000 years ago; dogs have coevolved with humans (practice Q19).

K^B mutation entered North American gray wolves from domestic dogs by hybridization; parallels EPAS1 from Denisovans.

Most breeds are a small subset of ancestral Asian dog diversity (e.g., Akitas, Shar-peis).

Cloning/cell reprogramming, ancient DNA sequencing, and genome editing of living relatives.

Diverts resources from living species; restoration is huge and uncertain; ignores habitat destruction, the main cause of extinction.