BSCI222 Final

CRISPR-Cas9

System made of gRNA and the enzyme Cas-9 which cuts DNA and then allows the cells DNA repair mechanisms to insert new DNA by using a provided DNA template

Gene Knockout CRISPR

CRISPR induced non-homologous end joining introducing random mutations and often leading to gene inactivation

Gene Knockin CRISPR

Cell uses a provided DNA template as a guide to insert new DNA

Gene therapy

treat genetic disorders caused by a nonfunctional gene by delivering missing gene’s DNA to the cells of the body

Huntington disease treatment

engineered virus containing miRNA that intercepts Huntington RNA is infused deep into the brain

Epigenetic Editing CRISPR

inactive Cas9 (dCas9) is fused to epigenetic enzymes and can use CRISPR to alter gene expression

Ex vivo gene therapy

Blood stem cells are collected from a patient then modified in a lab using CRISPR-Cas9 to correct the mutation and then returned to the patient through a bone marrow transplant

Multiplexed CRISPR

the same Cas9 molecule can be directed to multiple sequences at a time by providing more gRNA molecules

Sidewinder Method

Method used to build DNA fragments of unprecedented size and complexity rapidly and efficiently

AI effects on synthetic life

Helps scientists solve previously uncrackable scientific problems such as the shape of proteins

xenotransplantation

use of animal organs for people in need of a transplant. Pig DNA is emitted with synthetic DNA and CRISPR-Cas9 to humanize the organs

Colossal

Genetic company that is working on de-extinciton. Have created artificial uteri for thylacine marsupials embryos over halfway through pregnancy.

Multiplex genome editing at industrial scale

Colossal executes hundreds of simultaneous edits with 90% accuracy

X-32

microbe by the company Breaking which is genetically modified and can breakdown plastics

Synthetic Morphology

Making artifical multicellular structures. Can be done by tweaking morphogens, segmentation genes, TFs

Morphospace

The collection of possible stable body morphologies which has been largely unexplored by evolution

Xenobots

Synthetic living organisms made from frog stem cells and spontaneously self assemble

Anthrobot

Self assembling cluster of cellular spheroids derived from adult donor’s trachea

Alphafold and Synthetic Biology

Can predict how a protein, even synthetic ones, will fold and hence predict its behavior

RFdiffusion

network that are trained on millions of protein structures to give insight into the naturally occuring genetic sequences

Evo Designer Interface

predicts the effects of mutations in a gene and can decipher other features of complex genomes

Positive Eugenics

Selectively breeding people as done with domesticated animals

Negative Eugenics

Aimed to eliminate through sterilization or segregation those deemed physically, mentally, or morally undesirable

Polygenic screening

IVF is used to produce multiple viable embryos, then select between them to avoid genetic diseases

Polygenic risk score

A projection of someone’s risk of a conditions based on thousands of genes

IVF problem

Only produces 10 to 16 eggs, it is possible that this may be remedied by using iPSCs to produce gametes

PEPCK-Cmus

Mice engineered to express more PEPCK-C enzyme in their muscle which makes them better athletes and eat more but remain fitter. em

embryoids

Bioreactor acts as womb and mice or human stem cells transform into embryoids that show comparable growth and organ placement as regular embryos

Human genome project

Wants to identify all genes in human DNA, determine the sequences of the 3 billion nucleotides that make up human DNA and store this information in publicly accessible databases

Contig

A set of DNA fragments that overlap that form a continuous sequence of DNA

Allometery

Growth of body parts at different rates, resulting in a change of body proportions

Downside of genes that majorly improve desirable characteristics

Often pleitropic and bring tradeoffs. For example, mouse with enhanced N2RB gene which improves memory also has increased pain reception

power of informational view of life

looking at the commonalities and differences between genomes individuals and species to figure out what is important and what isn’t

Earth BioGenome Project

wants to sequence genomes of most known eukaryotic species by 2035

Syntenous

When chromosomes of different species have the same genes in the same order

paedomorphic

retaining juvenile characteristics, humans are like sexually mature juvenile chimps

Single Nucleotide Polymorphism

single nucleotide substitution that occurs in at least 1% of the populationH

Human and Chimp SNP differences

35 million differences, ~10,000 changed protein coding genes

Ticking of molecular clock

random mutations are inconsequential that accumulate at a steady rate that reflects the amount of time that has passed since 2 species had a common ancestor

Positive selection and molecular clock

Acelleration of the rate of change in some part of genome

Purifying selection in the molecular clock

no or little change in a part of the genome

Human accelerated regions (HARs)

Regions conserved in other animals that in humans have been mutated by an abundance of substitutions

Human conserved deletions (hCONDELs)

regions conserved in other animals that have been deleted

Copy number variants (CNVs)

Regions conserved in other animals that in humans have been duplicated in humans

HAR1

Gene most different between humans and chimps, encodes a lncRNA involved methylating genes in the brain stem cells which help put together brain folds

HAR2

2nd most different gene between human and chimps, enhancer that drives gene activity in the wrist and thumb during fetal development

HAR1984

Enhancer which encourages more neuron growth

Orthologs

homologous sequences found in different species and inferred to be descended from the same ancestral sequence

Paralogs

homologous genes in the same species and arise from gene duplication

Proconsul

the first ape

Rate of non-synonymous and synonymous substitutions

evolutionary rates of non-synonymous mutation are much slower than synonymous

dN/dS = 1

selective pressure is neutral

dN/dS < 1

negative selection

dN/dS > 1

positive selection

dN/dS

rate of non-synonymous over synonymous mutations in a gene which can be used to determine the selective pressure on mutations

ASPM gene

gene that regulates number of times neuronal stem cells divide and is one of the 10 protein coding genes that are critical for brain size and have evolved rapidly in humans

AMY1

encodes sailvary amylase which enhances starch digestion. More copies of the gene are found in populations that have been farming for longer

Fire affect on evolution

After discovery of fire, humans evolved to use fire to its greatest potential. changes to gut development and changes to a larger brain cavity and skull that didn’t need to support a large jaw

Sexual dimorphism

differences between males and females of a species

Eda and Eda receptor (Edar) influence on evolution

Controls hair structures. Changes in expression or protein sequence facilitate rapid evolutionary change

Why did homo erectus lose hair and get dark skin

Started persistence hunting in the savannah and loss of hair allowed them to be at lower risk of overheating. Darker skin protected them from the sun.h

hCONDEL and evolution

can achieve rapid evolution/paedomorphism by losing genes/regulatory regions that get you to next developmental stage so that you retain the juvenile body

Paleogenomics

the genomics of extinct things

Admixture events

interbreeding and genetic exchange between species. Likely played a role in the emergence of modern humans

Variation between homo sapiens

Most variation is in yoruba and san people. Asians and europeans have only a small amount of variation

Illumina

Machine which compares tiny fragments of archaic human DNA against modern human genome relying on synteny between species to map the archaic genome

Body shape in Sapiens vs Neanderthal

Neanderthals have a larger, bell-like chest cavity and wider pelvis. DCHS2, GL13, and Runx2 are top candidates for these differences

Neanderthal alleles in modern day

• Neanderthal allele come gives greatest likelihood for covid death

• protects against HIV infection

• skin genes which are related to UV adaption

Denisovans genes in modern day

Denisovans gave tibetans the gene EPAS1 which increases amount of hemoglobin the blood allowing life at high altitudes

Functions unique to modern humans

~30,000 SNPs, ~100 INDELs, ~3,000 regulatory regions, ~100 amino acids

These changes must be important for differences between archaic and modern humans

Differences in genes between modern humans and neanderthals

modern humans have genes that promote brain connectivity and aggressiveness

Differences in modern human behavior and neanderthals

• modern humans make more figurative art compared to abstract

• more innovative

• made the throwing spear

• had more nimble and efficient bodies

• shoulder blades optimized for throwing

Non-african shared ancestry

All modern non-Africans can trace their ancestry to a single small population emerging from Africa between 50 to 80 thousand years ago

Pedigree collapse

There is redundancy in your ancestors, there had to be interbreeding because if there wasn’t you would have more ancestors than possible

Special case inheritance

y chromosome is always passed from father’s father’s father etc, mtDNA always passed from mother’s mother’s mother etc

Human population genetics study subjects

mostly employs mitochondrial DNA and Y DNA. Y DNA more useful because it is bigger and mutates slower than mtDNA

Coalescence

Each stretch of genome that has not recombined can be traced back to a single Most Recent common ancestor (MRCA)

Haplogroup

A set of mutations on the mtDNA or Y DNA that define population groups

Where did europeans differntiate from

Mutations in east asian populations gave rise to europeans

Wolf and hominids

both wolves and people migrated from asia to europe. Each species domesticated one another evidenced by genetic changes

Why does human population have little variation compared to other great apes

Likely went through several bottleneck events, including one ~70,000 years ago

Apolipoprotein E gene (APOE) variants

E1 through E4 which helps adapts humans to their regional diets. E4 is ancestral allele that is good for traditional diet but increases heart disease with modern diet

Common functions of gene variants in the long lived

have genes that affect insulin IGF1 pathway

FOXO3

Master regulator of DNA defenses to stress responses. Most people over 95 have a specific allele called the longevity allele

Protective alleles

allels which override effects of harmful genes

Actionable variance

Helpful effects of alleles which can be replicated by drugs

Pharmacogenetics

genetic variation that underlie our responses to chemicals such as ability to taste

Cytochrome P450 genes

Some populations that have been farming for a long time lost the need for these genes because they breakdown poisons but they were not using taste to test their food for poison anymore

Problem with evidence based medicine

It is optimized for treating a statistically significant amount of people, however everyone’s genetics and hence biochemistry is different so it does not work for everyone

P4 medicine

Predictive, personalized, preventative, participatory. Using genetics of people to optimize their treatments and health

Genome wide association studies

Studying hundreds of thousands of genomes to analyze genetic variants with phenotypic traits

Haplotypes

Genetic region between recombination hotspots that tend to be conserved throughout the space

Selective sweep

Long haplotypes at high frequencey in populations indicate alleles that are so favorable they have spread rapidly through populations over last 5-10,000 years allowing no time for recombination

How long does it take for haplotypes to break down

5 to 10 thousand years

Hardy weinberg equilibrium

Allelic frequencies will not change in a closed infinitely large, sexually reproducing diploid population where random matings occur and natural selection is not involved

Hard Weinberg Equilibrium Equation

p² + 2pq + q² = 1G

Gene flow

Organisms and gametes that enter a population may have new alleles, or may bring in existing alleles but in different proportions than those already in a population

Positive assortative mating

people choose to mate with persons similar to themselves

Negative assortative mating

people avoid mating with those similar to themselves

The San people

most genetically diverse of any living humans studied