Genetics Midterm 2

Be able to draw a first and second division nondisjunction event of the sec chromosomes in the testis. Show both meiotic divisions and only show the sex chromosomes.

*Draw*

How many genes contribute to a particular trait?

- 4 million people have been analyzed to identify variation in genes that contribute to height - Genetic variation accounts for 80% of the variation in height - In this study almost 10,000 differences in the genome were found to contribute to height differences - These 10,000 differences account for 40-50% of the height variation in Humans (Looking at alleles with a high frequency)

What do they assay?

- Age-related macular degeneration - Alpha-1 antitrypsin deficiency - BRCA1/BRCA2 (selected variants) - Celiac disease - G6PD deficiency - Hereditary hemochromatosis (HFE-Related) - Hereditary thrombophilia - Late-onset Alzheimer's disease - Parkinson's disease

Controlling for the environment

- Compare the phenotypic correlation (concordance) of identical twins w/ non-identical twins. Same environment, different degree of genetic relatedness - Study twins that have been separated at birth. Compare them with each other, their non-adopted siblings, their birth parents and their adopted parents - Study identical twins separated at birth (rare)

Health report

- Health predisposition - Wellness - Carrier status - Traits

How do we study traits that are influenced by multiple genes?

- Height - Blood pressure - Intelligence - Risk of heart disease

Natural variation in the population makes a substantial contribution to chronic diseases such as:

- Hypertension - Type II Diabetes - Heart disease - Various dementia - Auto-immune diseases

What is the origin of variation in the human genome?

- Most of variation has been present 200,000+ years ago - DNA replication is not perfect - In humans, no negative selection of chronic illnesses 200,000+ years ago because not a strong selection for it (if die from heart disease don't care about fitness - Benign/neutral mutations --> about whether going to come down with disease

Variant examples

- Sickle cell anemia - Sjogren-Larson syndrome - Tay-Sachs disease - Tyrosinemia Type I - Usher Syndrome Type 1F - Usher Syndrome Type 3A - Zellweger syndrome spectrum (PEX1- Related)

How many Barr bodies are present in an XO Turner syndrome female?

0

3 Examples of the types of results our reports provide:

0 variants detected: likely not a carrier - this person could still have a variant not covered by this test 1 variant detected: carrier- this person could pass the variant on to his or her child Not determined: this test may not be able to provide a result in rare instances

Why aren't mutations fully penetrant?

1) Environmental factors/probability 2) Epistasis (the effect of the mutation is dependent on the genetic background in which it appears)

Genetic contribution to autism

1) Multigenic and highly heterogeneous • Very few cases monogenic 2) de novo mutations responsible for ~ 3% of cases but tend to be more severe • Of these 5-7% may be postzygotic 3) Copy number variants account for roughly 10% of cases

Autism factors

1) Significant de novo mutations 2) Specific combination of alleles can synergize and cause autism (significant negative fitness)

Unique Intergenic DNA

12% of Human Genome Intergenic regions often contain enhancers that can regulate genes 100,000s of base pairs away (from start of transcription) - Large area where enhancers can be placed

Protein coding sequences

2% of Human Genome DNA --> RNA --> Protein

Introns

26% of Human Genome

What is the chromosome complement of a monosomic?

2N-1 or 45 (human 2N=46 - 1 = 45)

AB & Alzheimer's

2X decrease in AB leads to a 5X decreased risk in Alzheimer's

APOE Alleles

3 Different APOE alleles in human population APOE2 APOE3 APOE4 (Alzheimer's disease- even chimps can get it) - individuals who are E4/E4 are 15X more likely to develop Alzheimer's This is probably a positive selection in humans

"Selfish DNA"

44% of the genome is composed of mobile "selfish DNA" whose main function is to propagate itself There is a constant competition between mobile elements that are transposing and the host genome that needs to maintain its integrity (have to transpose to stay alive, on the other side host genome, maintaining its integrity) How does the genome prevent mobile element transposition?

Alzheimer's disease heritability

60-80%

Heterochromatin

8% of Human Genome Heterochromatin DNA is generally not very active - In interphase, this type of chromatin are compact - Heterochromatin also has long stretches of repeat sequences called satellite DNA

More notes on SINE Elements

<500 bp 1.3 x 10^6 in the human genome Most common element in humans called All 300 bp only present in primates (10^6 copies) SINE elements depend upon functional LINE elements for their transposition All the All elements accumulated in the past 65 million years Early in primate evolution one of the All sequences transposed once in every birth. Now the rate is down to 1/200 births Genome has learned how to shut off activity of LINE elements (genome has come into balance)

Carriers

A carrier is a person who has one gene variant for a recessive health condition Carriers typically do not have the genetic condition. But, they could pass the gene variant down to their children

Haplotype

A group of DNA alleles (SNPs) that tend to be inherited as a unit. Haplotypes tend to be flanked by hot spots for DNA recombination

Genome-wide association studies

A large-scale analysis of the genomes of many people having a certain phenotype or disease, with the aim of finding genetic markers that correlate with that phenotype or disease.

23andMe

After you provide a saliva sample, 23andMe uses genotyping to analyze your DNA. This means we look at specific locations in your genome that are known to differ between people. We then turn those results into personalized genetic reports on everything from ancestry composition to traits to genetic health risks. - Ancestry - Health - DNA relatives (map)

Risks of Breast Cancer with BRCA1 or BRCA2 mutation

Age 40: BRCA1- 19%, BRCA2- 12% Age 50: BRCA1- 50%, BRCA2- 28%, Ashkenazi women w/ BRCA 1/2- 33%, General US population- 2% Age 60: BRCA1- 64%, BRCA2- 48% Age 70: BRCA1- 85%, BRCA2- 84%, Ashkenazi women w/ BRCA 1/2- 56%, General US population- 7%

Oocytes

All of the oocytes that a woman will ever have are generated before birth and the cells are arrested in Prophase I of Meiosis

Amyloid plaques

Amyloid plaques cause by processing of APP into AB which aggregates into plaques

Epistasis

An allele at one gene masking the effects of an allele at another age (original definition) Any type of genetic interaction between alleles at different genes (definition used in human genetics) In terms of breast cancer, individual could be lucky, because variant someplace in genes Genetic background effects - in mouse the same mutations assayed in different genetic backgrounds can have profoundly different phenotypes

Why does the frequency of autism correlate with the age of the father while the frequency of Down syndrome correlates with the age of the mother?

Autism is caused by new mutations which increase in the male due to continued cell division Down syndrome is caused by non-disjunction which increases with age in the female due to the eggs being arrested in Prophase I of Meiosis

BRCA1

BRCA1 is an essential gene and BRCA1 mutations are a loss of function mutations Conceptions that are homozygous mutant for BRCA1 fail to develop, but this is a rare event (.0006 X .0006 = 3.6 x 10^-7) BRCA1 mutations cause a dramatic increase in breast cancer rates but is not fully penetrant

Environmental factors/probability

BRCA1-/+ cells are normal 2nd event required --> loses + copy of BRCA1 This cell then can go on to form either a breast or ovarian cancer

Why is trisomy 21 (Down syndrome) the most common autosomal trisomy?

Because chromosome 21 is the smallest, it is the least likely to have a crossover Because chromosome 21 is the smallest, an extra dose of this chromosome is least deleterious

Viruses produce factors that:

Block the antiviral state - There is a constant battle between the host and the pathogen - This leads to rapid positive selection in both the host and the pathogen - This explains why populations exposed to new pathogens are adversely affected -Smallpox in the Americas -Syphilis in Europe -SARS-COVID world wide

Recap of Lecture 12

By combining GWAS and pedigree analysis it is possible to identify rare variants that substantially increase disease risk Variation in the levels of the AB peptide correlate with Alzheimer disease risk Rare alleles such as BRCA1 and BRCA2 can have a profound effect on disease risk Penetrance is the fraction of individuals with the disease risk allele who present with the disease Epistasis from alleles at other genes can modify the effects of disease risk alleles

Paternal influence

Children of older fathers tended to have a higher number of mutations that are not inherited from either parent

Intergenic DNA

Contain elements that define chromosomal domains Organized into larger domains - Different levels of organization of genome (humans, all plants)

Prophase 1 Meiosis

Crossing over occurs (homologous pairs swap pieces of chromosome, sister chromatids intertwine)

Variant

DNA difference between people

How do we find these rare (not on chips for GWAS) variants that dramatically increase the risk of disease?

DNA sequencing works very well but 1/1000 error rate With the assembly of the first human genome, it could then be used as a reference for "resequencing" individual genomes for diagnostic purposes It is important that the sequence is of high quality and has a few errors - Best error rate 1/1000, but 1/1000 is also the frequency of SNPs in the genome - How do you know whether a difference is a SNP or a sequencing error? Therefore, one wants every genomic sequence to be present on average 10X to 30X for an accurate genome sequence

Eugenics

Definition: a set of beliefs and practices that aims at improving the genetic quality of the human population - became popular in the UK/US in the early 20th century - used as a justification for the racial policies of Nazi Germany - used as a justification for forced sterilizations of the mentally unfit throughout the US and in North Carolina as late as 1974

What makes a calico cat mosaic?

Depending on activation --> white, orange, or black So cells expressing this x or this x - because of x-inactivation

Mutations & Siblings

Different mutations in affected siblings UBE3A encodes a protein involved in protein turnover STXBP1 encode a protein that binds syntax regulating neurotransmitter release THRA encodes Thyroid hormone receptor alpha KATNAL2 encodes a protein that regulates microtubules

Haplotype linkage to:

Disease susceptibility - two individuals with identical adjacent haplotypes with SNPs indicated by the bases above the line - one haplotype includes the IL23R gene - They are separated by a hot spot for recombination - A mutation substituting A for a G in the IL23R gene is the SNP that leads to susceptibility to Crohn's disease (vs. G- resistance to Crohn's) - Other mutations in blue lead to the generation of new SNPs and haplotypes - Impacts many generations - say looking at 8 individuals from the GWAS

SiRNA response is activated by:

Double stranded RNA Protein complex assembles on RNA --> 21 base pair fragments - PiRNA- shut off in germline - Trigger for initiated is double stranded RNA (For both SiRNA, PiRNA) - Cell assumes infected by virus w/ double stranded RNA - Dicer- chops up double stranded RNA - Provides specificity (fragments loaded into RISC) - Argonat - RNA nucleus, only base pairs w/ RNA fragments from double stranded RNA - This explains - how responds to invading RNA virus dsRNA --> shRNA w/ Dicer --> SiRNA duplex w/ Ago --> formation of RISC --> SiRNA/mRNA complex --> sliced mRNA "silencing"

Trisomy 21

Down syndrome

Examples of X-linked recessive traits

Duchene muscular dystrophy Hemophilia Color blindness

How much of the variation is due to heredity and how much is due to environment?

Environment effects: e.g. nutrition Genetic contribution- we can do a study with the students in the class and sending height + parents height and correlate

RISC

Enzyme that cleaves RNA Argonaute family protein Human genome mode of many transposable elements - elements that can transpose able to inactivate it - Germline of all animals - process of shutting down transposable events - LINE- transposable, promoter, get transcribed - Reverse transposable: allows LINE element to insert in a new place SiRNA --> RISC assembly --> unwinding of SiRNA --> mRNA cleavage

Dicer

Enzyme which recognizes and cleaves double-stranded RNA into miRNAs Chops up to 21 nucleotide fragments - Argonat - cleaves mRNA of virus and eliminates it when RNA infects cell starts single stranded - RNA viruses make template strand in order to work How do I distinguish RNA host + virus RNA? - single stranded - host - double stranded - trigger --> dices up --> loads to dicer --> destroys it

Euchromatin

Euchromatin is generally more active - In interphase they are generally not condensed

Changes in chromosome #

Euploid - N haploid - 2N diploid - 3N triploid - 4N tetraploid Aneuploid: - 2N-1 monosomic - 2N+1 trisomic

Adaptive immunity and antibodies recognize "foreign" antigens

Facilitates phagocytosis and the recruitment of complement

Imprinting by differential DNA methylation

Father: genes are differentially imprinted in sperm and egg Somatic cells of adult male and female maintain their genomic imprints Primordial germ cells- all reprints are erased In the eggs, imprints reset to maternal pattern even for the genes which come from father In the sperms, imprints are reset to paternal pattern even for the genes which come from mother Correct imprinting pattern is permanently established in zygote

If chromosome dose needs to be balanced, how is the difference in X dosage between males and females managed?

Females are mosaic (the presence of DNA alterations in only some of the body's cells) with most of one X chromosome inactivated in each cell early in embryonic development and this state passed on to daughter cells For example: female heterozygous for color blindness Half of the cells in the retina of the eye will have color vision in the other half will be color blind - Males have 1 X chromosome so if have allele --> have trait - Females have 2 X chromosomes but one turned off in each cell

Focusing on Regions

Focus on regions that make the largest contribution to disease risk - Chromosome 19 is important

Alzheimer's testing

For Alzheimer's they test for the e4 (RR) variant (Your risk for Alzheimer's disease also depends on other factors, including lifestyle, environment and genetic variants not covered by this test)

How does one disentangle Genetics + Environment or "Nature vs. Nurture" ?

For Mendelian traits that are controlled by a single gene with discrete characteristics, the "Heritability" of the trait approaches 100% and the genotype of the individual determines the phenotype For example with: - Huntington disese - Sickle cell disease - Duchene Muscular Dystrophy - Cystic Fibrosis

Falconer's formula & twins

From twin studies an approximation of H^2 can be calculated using Falconer's formula H^2 = 2X (correlation of Monozygotic twins) - (correlation of dizygotic twins) Assumes monozygotic + dizygotic twins experience equivalent environments But, parents may treat identical twins differently than fraternal twins

GWAS & Crohn's disease

GWAS for several genes that contribute to Crohn's disease IL23R = Interleukin 23 receptor, which regulates inflammation

Recap of Lecture 13

GWAS studies usually only identify a fraction of the genetic contribution to variation in a particular trait 23andMe has greatly expanded the number of people taking part in GWAS studies The lower cost of genome sequencing makes it feasible to sequence parents and progeny "resequencing" This allowed the identification of new mutations that have been implicated in diseases such as autism

How was the study done?

GWAS- Genome Wide Association Study Based on variation in the human genome usually SNPs - SNP single nucleotide polymorphisms - SNP sample GATC GAATGC vs. GATC CAATGC Variation in the human genome - 10-30 million SNPs present at a frequency of at least 1% in the human population - Genotyping done using chips that can assay a million variants across the human genome

Genetics & Different Ethnicities

Genetic conditions affect certain ethnicities more than others Our reports can provide more detailed information for ethnicities that have been well studied - particularly useful for Europeans

Minnesota Twin Studies

Genetic influence on the following traits: - Intelligence: 0.7 correlation - Alcohol + drug abuse: 0.78 correlation - Vocational interests: 0.5 correlation - Personality traits: 0.5 correlation

Imprinting leads to differential gene expression

Genomic imprinting - preferential expression (or repression) of one parental allele - epigenetic modification mechanism (CpG methylation)

SRY+

Gives rise to testis or ovary

Heritability of Autism

H^2 = 2X (correlation of Monozygotic twins) - (correlation of dizygotic twins) H^2 = 2X (90%-4.5%) = 171%? Variation is additive - allele with high probability will be additive (need to add all together) - identical twins will always have that certain combination

Risk of Down syndrome in Live Births vs. Age

Higher probability of non-disjunction events as maternal age gets older

Recap of Lecture 10

Human genetic variation comes from three sources: 1) Genetic variation that was present in the original human population 200,000 years ago 2) New mutations that have accumulated over time 3) Variation introduced through matings with Neanderthal and other related hominids Genome wide association studies (GWAS) became possible with the sequencing of multiple human genomes

Discussion Topic: Personal genome sequencing- Nebula genomics

I was really interested by this article, and was definitely surprised by the statistic that 99.9% of people's genes are the same, leaving 0.1% to be where the human variation is. I thought that this article gave me more perspective on some of the pros and cons of genetic sequencing, but I definitely think that it seems like there is not much one can change if they find out about certain genes and mutations, and so it doesn't seem worth it. For example, in the article it says that only 1 or 2 percent of people get an "actionable result" meaning something that they can change. In the example given about Factor V. Leiden which makes someone 6 times more likely to have a blood clot, I definitely think that this can freak people out when it is not that big of a deal. In this case, blood clots are already super rare with a 1/1000 risk whereas this person would have a 6/1000 risk which is not super different and can scare people unnecessarily

Autism (twins)

Identical twin: 90% Non-identical twins: 4.5%

Monozygotic twins

Identical twins - genetically identical

Schizophrenia

Identical twins: 40-50% Non-identical twins: 10%

Hypertension

Identical twins: 62% Non-identical twins: 48%

Alzheimers (twins)

Identical twins:78% Non-identical twins: 39%

Chromosome 1 explanation

Identifying variation in population --> identify corresponding gene Probability of having crossover? Analyze hotspots If have polymorphism, higher probability of having Crohn's Identify SNPS which correlate with haps (responsible for susceptibility) A- high susceptibility G- low susceptibility

What if both parents are carriers?

If both parents are carriers, their child may inherit two variants and have the condition - 50% chance- child is a carrier - 25% chance - child is not a carrier - 25% chance- child has the condition

Article 1: New Concerns raised over value of genome-wide diseases

If you compare the genomes of enough people with and without a disease, and genetic variants linked to the disease should pop up GWAS: genome-wide association studies —> found that many GWAS hits have no specific biological relevance to disease and wouldn't serve as good drug targets - instead these 'peripheral' variants probably act through complex biochemical regulatory networks to influence the activity of a few 'core' genes that are more directly connected to an illness Assumption that when you find something it should be directly involved in the disease you're studying - "When you start to think that all of the expressed genes in a tissue can matter, it becomes untenable that there's a simple biological story for each one. Should instead spend time devoting their efforts to mapping regulatory networks in cells GWAS as finding genes that contribute to the risk of developing conditions such as obesity Even for traits that are known to be highly heritable, suggesting that they have a large genetic influence- the cumulative influence of all the DNA variants spotted by GWAS doesn't fully explain the variation seen between people Found that GWAS hits in DNA regions that are expressed in the particular cells relevant to the disease- neurons for schizophrenia and immune cells for the two auto immune diseases This doesn't mean that researchers should stop carrying out GWAS even if peripheral to a disease- it still helps scientists knit together the biological networks implicated in a disease and discover things

Why do non-disjunction events increase with the age of the mother but not the father?

In females, all the germ cells are arrested in Prophase I of meiosis by the time of birth. Over time non-disjunction events occur In males, stem cells continue to produce sperm

Imprinting

In genes that undergo genomic imprinting, the parent of origin is often marked, or "stamped," on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA - the vast majority of genes are not imprinted - a small number of genes are imprinted either in the sperm or egg - if heterozygous for imprinted - if imprinted allele not going to be expressed (doesn't do anything) - Heterozygous --> methylated + imprinted

More on Heterochromatin

Included within heterochromatin are the centromeres that attach to the spindle and the telomeres that cap the ends of chromosomes 1) Need telomeres so ends of chromosomes don't get eroded 2) Microtubules bind (proper segregation of chromosomes)

Human genome organization

Introns LINEs SINEs Misc. unique sequences Misc. heterochromatin LTR retro-transposons DNA transposons (some of DNA elements "dead"- lost ability to transpose from genome, multiplying + moving - will slowly disappear) - remains of selfish elements during primate evolution Simple sequence repeats Segmental duplications

Why are there introns?

Introns only exist in eukaryotes and are not present in bacteria Alternative splicing can produce multiple proteins from a single gene - this allows a single gene to make multiple different combinations

In humans most aneuploids are:

Inviable

XXY

Klinefetler syndrome, phenotypically male

What do our tests help with?

Knowing your carrier status is important when starting a family Our tests do not diagnose any health conditions - our reports can help you understand your chances of carrying a variant that could be passed down. This can be helpful for you or your relatives when having children

LINE Elements

Long Interspersed Nuclear Elements - 20% of Human Genome Three families ~ 5 x 10^5 copies in Human genome. Some L1 elements have active retrotransposase

Males & Meosis/Mitosis

Males are continually generating new sperm from germ line stem cells and are therefore at greater risk of accumulating mutations over time

What type of genetic defects increase in frequency with age in the gametes?

Males- spontaneous mutations Females- chromosome non-disjunction

With increasing age, which type of mutations accumulate in Males and Females?

Males: errors in DNA replication Females: non-disjunction events

Barr body + Methalyzation

Methalyzation on inactive X- causes Barr body

Heritability of Autism

Monozygotic twins: 0.8 concordant Dizygotic twins: 0.2 concordant Falconer's formula: H^2 = 2x (Correlation of monozygotic twins) - (correlation of dizygotic twins) 2 x (0.8 - 0.2) = 120%

Calico Cats

Mosaic expression of X chromosomes is most easily observed in calico cats which are almost always female

Where does most of the heritability of autism come from?

Most of the heritability of autism comes from a large number of common variants with low effect sizes - this is very difficult to map and has only been done recently

Genetic contributions to Autism

Multigenic and highly heterogenous - very few cases monogenic De novo mutations for ~3% of cases but tend to more severe - of these 5-7% may be post zygotic Copy number variants account for roughly 10% of cases

Protective variant at APP gene

Mutation --> A673T is present at ~1% in Scandinavian populations and 0.02% in the US population

Candidate genes where variation contributes to autism risk

NEGR1, PTBP2, CADPS, KCNN2, KMT2E, MACROD2

Mutations & Autism

New mutation in autism relevant gene shared between affected siblings SCN2A encodes a subunit of a voltage gated Na channel

Recap of Lecture 9

Non-disjunction events during meiosis lead to aneuploids - important- critical have balanced gene expression The frequency of new mutations increases with the age of the father Females are mosaic due to random inactivation of one of X chromosomes. A small portion of the X is not inactivated and accounts for Turner + Klinefetler Syndrome

Dizygotic Twins

Non-identical twins - share 50% of their genes in common

1st division non-disjunction vs. 2nd division non-disjunction

Nondisjunction in meiosis 1 and 2 is that during meiosis 1, homologous chromosomes fail to separate while in meiosis II sister chromatids fail to separate

Methylcytosine

Normally silencing mechanism - not expressed - important in imprinting - Different sites on mother/father are methylated

What about other traits (not Mendelian traits)?

Other traits are regulated by multiple genes where the variation at a single gene only makes a modest contribution

LINE Element Transposition

Overview: - double strand break - LINE inserts into break - functions as template - Reverse transcriptase - uses RNA template to make DNA - Replaces RNA w/ DNA (now transposition) Line Element --> transcription --> translation --> reverse transcriptase tranposase --> reverse transcriptase/transposase makes double strand break somewhere else in genome --> RNA of LINE element inserts in break --> Reverse transcriptase/transposase makes DNA copy of Line element --> RNA strand replaced by DNA

SINE Element Transposition

Overview: exactly same thing (as LINE) - uses template to make DNA copy

Why does the mother carry the mutation and is unaffected whereas the son is affected?

Perhaps the mutation has nothing to do with autism Differences in genetic background between the mother and the son Males are more susceptible to autism than females. Boys 3-5X more likely to have autism than girls

SNPS and Human Genomes

SNPS are identified by comparing the DNA sequences of different individuals SNPS are distributed throughout all the chromosomes

Why is Minnesota twin studies controversial?

Scientific results can have important implications for policy If intelligence is primarily determined by genetics, why invest in social intervention programs? - Most variation is between individuals - A major genetic component does not eliminate the substantial contribution of environment Eugenics movement

How do we identify the genes with new mutations that cause autism (5%) ?

Sequence parents and children: Study of autism in 85 families in which the parents were unaffected and two children had autism Identified mutations in 46 genes thought to be relevant for autism, of these 16 were new mutations 70% of the affected siblings had mutations in different genes

Sex determination

Sex determination involves a complex cascade of events that do not always result in a binary decision

SINE Elements

Short Interspersed Elements - A common class of transposable elements in humans, these nonautonomous transposons are incapable of independent replication but rather rely on genes encoded by autonomous transposons elsewhere in the genome.

Nucleic acid recognition based immunity

SiRNA targets and cleaves RNA (organisms develop to attack RNA viruses) - Activated by double stranded RNA - Targets RNA viruses PiRNA targets and cleaves RNA and silences genes (in germline- which targets transposable elements) - Activated by double stranded RNA - Silences transposable elements in the germ line (identifies the mRNA from transposable elements + discards them)

A comparison between preexisting variation and new mutations (denovo- not inherited)

Single-nucleotide variants: inherited variant: 3.5 to 4.4 million De novo mutations: 44 to 82

Where is the missing 30-40% of genetic contribution to height variation?

Studies on a subset of the human genome suggest that missing genetic contribution to human height variation is due to alleles that are very rare <1% and have a stronger effect than the more common variants (not on gene association apps because so rare) This appears to also be true of genetic variation that contributes to disease susceptibility

Nutrition and epigenetics

Suboptimal maternal nutrition: Epigenetic resetting --> epigenetic changes in soma --> Epigenetic changes in germline Excess nutrition: Epigenetic set and stable- programmed to retain energy storages --> anticipating famine (epigenetic need to be set) Altered gene expression --> Onset of metabolic syndrome --> Inheritance to next generation

Tau Tangles

Tau tangles are caused by hyper-phosphorylation

Article 2: Opinionome- the past and future values of GWAS

The 3000 genome-wide association studies published over the last 10+ years have revealed more than 39,000 genetic links to human traits and disease. Has all the effort been worth it? And is there a future for GWAS? Have revealed potential connections between thousands of areas of the human genome and specific traits or common diseases- autism, cardiovascular disease, diabetes, height + psychiatric disorders Makes it hard for researchers to prioritize the list of "hits" for further study because provides a list of genomic regions associated with a trait or disease Is it worth it Perspectives: GWAS allowed a major shift in how we map disease traits - before GWAS, the tech available allowed for low resolution approaches like linkage mapping GWAS- capability to screen for disease-related genes in the general population in a high resolution Will all 39,000 plus associations found so far result in discovery of the risk or protective alleles or treatment targets for any given disease- no but still helpful - can still show the landscape of a disease

What about the Y?

The SRY gene on the Y specifies male development Female development is the default state

Why does the presence or absence of a Y chromosome determine sex in mammals?

The Y chromosome carries the SRY gene that specifies male development

Chips

The chips only assay SNPs They will not pick up CAG expansions as in Huntington's disease, nor will they pick up deletion mutations as can occur with BRCA1 and 2

Does the Y do anything else?

The dose of the Y contributes to height 1/1000 males are XYY (extra Y) and tend to be unusually tall XYY individuals are generated by chromosome non-disjunction events

Why do XO females present with Turner syndrome?

The entire X chromosome is not X inactivated and females require that second dose of the part of X that isn't inactivated to be normal

Recap of Lecture 11

The human genome is divided into segments that are flanked by hot spots of recombination These segments are called haplotypes and tend to be inherited as units Specific combination of SNPS can be used to identify haplotypes Genome Wide association studies (GWAS) have successfully identified variation across the human genome that contribute to disease susceptibility Alzheimer's disease is characterized by two pathologies: Amyloid Plaques and Tau Tangles

A Family Portrait

The human lineage and the chimp lineage split about 7 million years ago

Barr body

The inactive X is coated with a larger non-coding RNA (Xist) which leads to the deacetylation of histones and the methylation of the DNA shutting off most of the genes on the inactive X This blob called Barr body has genes on the chromosome that can't be expressed. Example of x-inactivation Example: Olympics --> if didn't have this then not considered a "female" for the Olympics

RNA virus Replication

The key difference between the negative and positive sense RNA virus is that the negative sense RNA virus comprises viral RNA, which is complementary to the viral mRNA, while the positive sense RNA virus comprises viral mRNA, which can be translated into proteins directly - has to make double stranded RNA (means have been infected) - initiates cascade of events

Why are there orange and non-orange calico cats?

The orange/non-orange coat color gene is on the X chromosome The patterns of orange and dark pigmentation correspond to cells that descended from individual cells that inactivate one or the other X chromosome

piRNA pathway

The piRNA pathway is a variation on the SiRNA pathway specifically targeting transposable elements in germ line shuts down LINE from future transposing but not permanent LINE Element --> transcription --> reinsertion into the genome --> translation into reverse transcriptase --> LINE element in piRNA cluster --> Promoter (make RNA in opposite direction) MIWI2/antisense piRNA - cleaves LINE element mRNA and represses LINE element expression

Epigenetics

The study of heritable phenotypic changes that do not involve alterations in the DNA sequence - One form of epigenetic is the methylation of Cytosine at CpG sites, which generally leads to gene inactivation - During X inactivation the inactive X chromosome is heavily methylated at CpG sites (leading to this chromosome not being expressed)

Why do XXY males present with Klinefetler syndrome?

There is a part of the 2nd X that is not X inactivated and this provides an extra dose of these genes that isn't present in normal males

Genetic architecture of Cancer Risk

This genetic risk profile for cancer calls into question the idea that long standing variation in the human population is responsible for major differences in disease risk Instead, more recent mutations that are present at low frequency in the human population may be responsible for significant differences in disease risk. (EX: BRCA1 ~ 0.06% ~ 1/2000- Responsible for 5% of breast cancer cases in women under 40 (increases risk ~ 100 fold)

Why does the risk of non-disjunction events increase with age in females while the risk of new mutations increase with age in males?

This is a consequence of the distinct biology of the female and male reproductive systems in humans

Why do non-disjunction events increase with age in the female germline, while spontaneous mutations increase with age in the male germline?

This is a consequence of the distinct biology of the female and male reproductive. systems in humans. - All of the female oocytes are arrested in Prophase I since birth. - The male germline is constantly undergoing cell division so mutations accumulate. They are continually generating new sperm from germline stem cells and are therefore at greater risk of accumulating mutations over time.

How does the genome protect itself against viruses and transposable elements?

Three types of immunity - Innate immunity (Toll-like receptors, present in all animals) - Adaptive immunity (Antibodies, T cell receptors- vertebrates - Nucleic Acid recognition based immunity (ubiquitous)

Innate immune response to viruses

Toll-like receptors recognize virus nucleic acid (DNA or RNA) Leads to the expression of InterferonB IFNB secreted and bound to receptors on adjacent cells Activation of IFNB receptors cause cells to enter an antiviral state blocking virus replication

X0

Turner syndrome, phenotypically female

Recap of Lecture 14

What's in the human genome? Only 2% of the human genome is translated into proteins (initial RNA --> exons + externs (splicing system) Protein coding regions are split up in segments called exons, which are separated by introns that are removed by splicing to generate the mRNA Centromeres and telomeres are made up of Heterochromatin Methylation of cytosine at CpG sites is an epigenetic mark that silences the inactive X, marks imprinted genes and can set gene activity during gestation Line and Sine elements are the only active transposable elements in the human genome Line elements express reverse transcriptase that catalyze the movement of Line and Sine elements How does the human genome defend itself vs. parasites + transposing?

Why aren't XO and XXY individuals normal?

XO = X: factor of 2 decrease in dose of non-inactive X XXX = X: factor of 1.5 increase in dose of non-inactivated X XXY= X: factor of 2 increase in dose of non-inactivated X

Which of the individuals are phenotypically female: XO, XX, XXX, XXY, XYY?

XO, XX, XXX

What is the genotype of a male calico cat?

XXY

When looking at the cells from a male patient, you notice that the nuclei contain Barr bodies. What is the genotype of this male?

XXY

A second division nondisjunction event in the male gives rise to one sperm that is YY and a second sperm that has no sex chromosome. Assuming these sperm fertilize normal eggs, what will be the genotypes and phenotypes of the resulting progeny and will they present with any syndromes?

YYX phenotypically normal Male (tend to be taller) X or XO phenotypically female with Turner syndrome

Is one allele more frequently associated with the phenotype than the other allele?

Yes

Candidate gene approach --> Are there alleles of Tau, APP or the Secretases that correlate with Alzheimer's disease?

Yes Early-onset FAD (~5% of Alzheimer's cases) Dominant mutations in: - APP - PSEN1 (encodes a core protein in y-Secretase) - PSEN2 (encodes a second core protein in y-Secretase) All lead to increased levels of AB - the variation we see for higher risk for Alzheimer's because of accumulation of AB

Illumina Microarray

analyzes ~1 million SNPs related to ancestry and susceptibility to disease

Spliceosome

another RNA-protein machine which may be a link back to the RNA world (machine which takes in initial RNA molecules)

SNPS

associated with whether susceptible to disease - looking for specific SNPS that correlate with the phenotype of interest

Antiviral state

cell capable of inhibiting viral protein synthesis due to interferon activation

QTL mapping in Humans

deCODE Genetics - Iceland - 160,000 participants - Geneaology to 1000 AD - Access to medical records Typically their studies involve several thousand affected and unaffected controls Genes identified contribute to a wide variety of diseases Moving from SNP analysis to whole genome sequencing Combination of genealogy + GWAS --> greater power to identify alleles that are rare but have powerful affect

SINE

degenerate versions (DNA sequence depends on LINE elements) - business part - can't move without LINE element which provides enzymatic activity

Cost of sequencing a human genome has:

gone down over the past 20 years

Heritability

how much of variation we see in a population is related to Genetics

Evolution of APOE alleles

human-chimp ancestor --> ancestral allele --> derived allele --> derived allele

Aneuploids

lacking one or more chromosomes or having one or more extra chromosomes

LINE

like reverse transcription- enzyme which allows to insert in a new position - mediates transposition - RNA --> DNA

piRNA pathway is essential to:

maintain the integrity of the germ line genome - Loss of the piRNA pathway in leads to mobilization of transposable elements - The new insertion sites of the transposable elements cause mutations and dramatically reduces fitness

Non-disjunction events

mis-segregation of chromosomes (x and y go in same direction)

XYY

normal male

XXX

normal, female

How retrotransposons copy and paste

original element --> RNA copy --> staggered cut --> DNA copy

Recombination

over evolutionary time recombination gives rise to different allelic combinations occurs during Meiosis Prophase 1- homologous chromosomes pair and exchange DNA segments - If process were random --> would make random distribution because that's not the case - blocks that are flanked --> tend to be inherited from one generation to the next

Transposase

protein which allows transposing to happen (transmitted onto next generation)

Penetrance

the fraction of individuals who carry the mutant allele and present with the mutant phenotype

Chromosome 21

the smallest chromosome and therefore the most likely to not have a crossover and the one whose over-expression is best tolerated (3 chromosomes instead of 2)

Aneuploids are:

usually a consequence of non-disjunction events (progeny goes through normal meiotic division) each of gametes have each of autosomes (regular chromosome) but no sex chromosomes

SNPS

variations in the DNA sequence that occur when a single nucleotide in the genome is altered - variation at multiple places that determines susceptibility

Heritability of Prostate cancer

~60% But all the GWAS studies only explain 1/3 of the heritability