Moving!

We are less than a week away from the move, so I'm writing one more post and then there might be some radio silence while we get settled on the west coast.  Here are some topics that have come up in conversation, written Q & A style.:

Q:  Wait, didn't you just buy a house in Virginia?
A:  We did just buy our house 6 months ago.  Fortunately, there is a robust rental market in Virginia Beach and so we were able to rent our house out pretty quickly.  The tenants, who we really like, signed a 5 year lease.  So that worked out as well as it possibly could have, considering the circumstances.  Thanks to anyone who prayed about this for us.

Q:  How are you getting across the country?
A:  The kids and I are flying across the country next week.  After we leave, Kenny will pack up the house, clean it for the renters, and then drive across the country.  (Awesome husband award!!)  He will pack our stuff into a storage box (like a POD but different company), which will ship out to Reno and wait in storage until we find a home.  We will stay with Kenny's parents until we find a place to live.

Q:  How's it going getting Joshua's school / care switched over?
A:  The school switch, to my surprise, could not have been easier.  I e-mailed the woman in charge of Reno's special education preschool program with a copy of his current IEP, and she agreed to enroll him in the appropriate school under the terms of his Virginia IEP.  We are going to wait to start him in school in Reno until August, since this move is going to be a massive transition, and in the meantime he will get some private occupational therapy and some extra quality time at home with me and Zoey!  The kids are at a very sweet age right now, both individually and as a sibling unit, so this will be a fun summer for me to get 4 months with Josh at home.  The medical care switch should be fine, too.  Joshua spent the first 9 months of his life living in Reno, so not only do we know that they have the appropriate specialists, but he's already seen most of them several times.

Q:  How are you feeling about everything?
A:  I'm really looking forward to arriving in Reno.  We're in that funny in-between stage right now: we're finishing things up in Virginia - saying goodbye to people daily, squeezing in last minute appointments, and getting all our stuff in boxes; while at the same time, making plans for our life in Reno.  It's an emotional rollercoaster of excitement and sadness, depending on what activity you're doing in a given moment, and I'm ready to get back on more of an even keel.  I'm looking forward to all the things described in this blog post.  I'm hoping to fit in one more trip to the beach while we're still in Virginia.  I'm also REALLY looking forward to getting the day of flying solo with the kids over with.

If you have any tips about cross country moves or cross country plane flights with young kids, please leave them in the comments!

Unit 5: Schizophrenia

This week, my Behavioral Genetics class focused on Schizophrenia as an example of how behavioral genetics explains a particular phenotype.  Here are the notes I would like to remember from this week.  Also, below this week's notes is a question I asked in (virtual) Office Hours and the professor's response:

Characteristics of Schizophrenia:

• Positive Symptoms (presence of something that is not normally there):  Thought disorder, delusions, hallucinations, movement disorder
• Negative symptoms (disruption in normal behaviors or emotional response):  Inappropriate affect, deterioration of social behavior, 
• Cognitive symptoms:  Impairments in working memory, attention, executive function
• Tends to start in late adolescence or early adulthood.

Epidemiology of Schizophrenia

• Males are at greater risk for all neurodevelopmental disorders, including schizophrenia.  
• Correlation with lower social classes (but not necessarily causation).
• Frequency of schizophrenia is similar across different countries and ethnic groups - but immigrants have higher rates of schizophrenia than non-immigrants.  
• Reduction in fertility

Twin Studies tell us about:  

1) Genetics of Schizophrenia

• Rare event to find twins (2% of population) with schizophrenia (1% of population).  
• Genetically identical twins are usually less than 50% concordant for schizophrenia - if one twin has it, it's (close to but) less than half the time that the identical twin also has it.
• They show that there is a genetic component, but that environmental factors also important.  
• Risk of schizophrenia increases exponentially with degree of genetic relatedness.  (Not just a linear increase, like in autosomal dominant diseases.)
• Exponential tells you that it must be multiple genes causing schizophrenia.  
• Seems to be between 60-80% heritable.  

2) Environmental Factors Related to Schizophrenia

• Shared environmental influence doesn't seem to be very important:  majority of schizophrenics do not have siblings with schizophrenia, being reared by an adoptive parent with schizophrenia does not increase risk of schizophrenia
• Non-Shared:  MZ concordance is around 50%.  Individuals with schizophrenia have larger ventricles.  Low birth weight, obstetrical complications, maternal conditions (such as malnutrition or flu).  

Identifying Schizophrenia Risk Alleles

1.  The Positional Cloning Strategy

- When you know a trait is heritable, find the position on the chromosome, then identify the genes on the chromosome.  This works well for traits that are caused by a single gene, but not so well for traits that are caused by multiple genes.  

-Candidate gene studies:  target specific genomic regions when looking for association.

-Leading study on this came up with no significant findings.  

2. The GWAS (Genome Wide Association Stragegy)

- The association between each SNP and the phenotype is tested using an array.  

- Learn that the effect of any specific variant is small, even if a trait is mostly heritable.

- Identified risk alleles tend to be very common (many of us are carrying some of them, but just not enough to express the phenotype of schizophrenia) - individually, they have small effects - but they implicate certain pathways.

- They have only figured out about 5% of the heritability of schizophrenia.
- This type of study misses rare variants and structural variants such as CNVs

3. Rare Variants and CNVs

- Rare variants:  There are certain disorders that are more likely when father is older.  With age, men produce more mutations in their gametes than women.
- 22.Q.11.2 syndrome given as example of CNV - individuals with this deletion have 20-30% likelihood of having schizophrenia, and 1% of people with schizophrenia have this deletion.
 -Note:  "De novo" means that neither the father nor the mother has the deletion, but somehow in cell reproduction, the child gets part of one of their two chromosomes cut out.  

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Here's the answer to my office hours question from last week:  Why is it that children with the same genetic deletion can have very different phenotypes?  (So for example, in 4q, many but not all kids have heart problems, Pierre Robin Sequence, finger and toe anomalies, etc.  Why wouldn't it be all or none if they have the same set of missing genes?)

1.  It's not always the same exact region that's being deleted - even if you have a matching number on the micro-array, these copy number variants cover millions of bases - so the deletions have significant overlap, but they are not actually exactly the same and there may be significant differences happening at the boundaries.  

2.  If you only have one whole copy of a particular chromosome (and the other contains a deletion), then the allele you have on the copy without the deletion becomes really important.  It gives an opportunity for recessive alleles to be expressed, when they would often be "overruled" by the matching dominant allele.  

3.  Genes at other regions of your genome can be interacting or impacting expression.  

Behavioral Genetics Week 4: The Human Genome

This week in my Behavioral Genetics class, we learned about the Human Genome.  This included several lectures on genetic variation, which was very interesting to me because it's directly pertinent to Joshua's situation.  It's interesting to see (even in a lightning speed flyover on the subject) how far the field of genetics has come in the last 20 years, and how rapidly it's progressing.  The professor said that he expects knowledge of the human genome will revolutionize medicine, which is exciting. Without further ado, things I want to remember about this week's lesson on the Human Genome...

• DNA provides a code for building proteins, chains of amino acids
• DNA (double strand) is transcribed into RNA (single strand), then translated into proteins.

Gene Structure:
1.  There is an orientation:  5' (upstream) to 3' (downstream).
2.  Upstream (5’) is a regulatory region, a promoter that determines which strand of DNA will be used and where the gene starts.
3. Genes are not continuous DNA sequences, they contain introns and exons (Exons – Expressed, contain the protein coding sequence; Introns – Intervening sequences)

3 surprises about the human genome:
1.  Most of the human genome is non-coding (98.5%) (but non-coding does not mean non-functional).
2.  Humans have a small number of protein coding genes. (Humans have around 21,000 genes.  This is slightly more than a fruit fly and slightly less than a mouse.)
3.  Comparative genetics - "we're all essentially identical twins".  All humans share 99.9% of DNA the same as each other.  But think about overall scale - even though we're mostly the same overall, there are still 6.4 million differences.  Very small changes in our DNA can have rather significant effects.

Genetic Variance Among Us

• Insertions / Deletions - small number of bases (less than 100) missing or added - this is very common
• Copy number variants - large segments of DNA (at least 1000 bases) have been deleted or inserted.  Ex:  22q11.2 (missing about 3 million bases) [This is the type of genetic variance that Joshua has.]
• Aneuploidy - having an extra or missing chromosome (ie Down's Syndrome).  These are fairly rare.
• Organization - differences in how DNA is organized - inversions and translocations.

The Unique Case of the X Chromosome

• Women have two X chromosomes.  Men have an X and a Y chromosome.  
• X Chromosome has a lot more protein producing material than Y chromosome. (2,000 v. 80)
• But women do not produce a lot more protein products than men, because in women, only one X chromosome is active - the other becomes inactive.  
• Different cells will have different X chromosomes turned off.  The timing is random, but it happens early in embryonic development, and once it happens it's permanent - when those cells duplicate, the same X will be turned off.   
• This show that there is a mechanism of genetic regulation.  

Prader Williams and Angelman's:  Two Different Genetic Disorders on the Same Part of the Genome

• Prader Williams:  uncontrolled eating, low muscle tone, cognitive dysfunction.  15q11.2
• Angelman's:  movement and language disorder, behavioral (happy).  Also 15q11.2
• Even though these deletions are de novo, in PW it's always the father's chromosome that's deleted.  In Angleman's, it's always the mother's chromosome that had the region deleted.
• Why should it matter if it was father's or mother's chromosome?
• There are regions where whether you inherited from father or mother makes a very big difference in the expression of the gene.  About 1% of our genomes are imprinted this way.
• Another possibility: uniparental disomy - the child ended up with two chromosome 15s from just the mother, or from just the father, rather than one chromosome 15 from each.
• Another example in nature of genes expressing very differently depending on whether they were inherited from the father or the mother:  ligons (father is lion, mother is tiger - they are large) are very different than tigons (father is tiger, mother is lion - they are quite small).

Epigenetics 
Epigenetics is the study of genetic regulation - differences in DNA expression that is not due to difference in the DNA sequence.  3 examples of this:
1.  X chromosome inactivation
  - Occurs early (in first couple weeks of embryonic development)
  - It's stable - once it becomes inactive, it stays that way
2.  Imprinting - some genes only expressed if inherited from mother, some genes only expressed if inherited from father.
  - Once again, it happens early and it's stable.
3.  Gene expression pattern - what differentiates a muscle cell from a liver cell from a blood cell.
  - Again, happens early and it's stable.

Could factors in our environment cause epigenetic effects?
 - Yes.  Some examples:  maternal malnourisment (increased sensitivity in early embryonic development), grooming in a mice study,

Behavioral Genetics Week 3: Heritability

This was week 3 of my Behavioral Genetics class, and this was the first week where (at times) I felt lost.  For Week 3, the professor taught some of the basic vocabulary words of genetics, gave a basic explanation for how heritability is calculated (this is the part where I got lost and I'm not even going to make an attempt to explain or remember it), and introduced the concept of gene environment interaction.  Part One of this blog post is vocabulary that I want to remember, so feel free to scroll on past.  Part Two of this blog post talks about gene-environment interaction, which is more generally interesting.

Part One:  Genetics Vocabulary

• Gene - a functional unit of inheritance
• Allele - alternative forms a gene governing a specific character can take (ie Y and G for color)
• Genotype - the two alleles one inherits
• Homozygotes - YY or GG
• Heterozygotes - YG or GY
• Genes are located on chromosomes, which are located in the nucleus of all our cells.
• Chromosomes 1-22 are autosomes. (Numbered roughly from largest to smallest.)  The third chromosome is the sex chromosome.
• Recombination - exchange of genetic material between homogous chromosomes
• Variance:  an index of the degree to which individuals differ for a quantitative trait 
• Biometrics:  Take a phenotypic variance and find what portion is associated with genetic variance and environmental variance.
• Additive genetic effects - the effect this gene adds does not depend on what genes it pairs with
• Non-additive genetic effects - the effect this gene adds does depends on what genes it pairs with
• Shared Environment - things individuals growing up in the same home share (income level, parents approach to child rearing, neighborhood)
• Non-shared Environment - environmental effects that individuals growing up in the same home do not share (peer group, accidents, differential parental treatment to each sibling

2 different heritability measures:

• Total heritability - indexes the effect of all genetic contributions.
• Additive heritability - measures the effect of additive genetic contributions.

ACE
A = Additive
C = Shared environmental factors
E = Non-shared environmental factors

• A usually explains at least half of traits (moderate to large effect)
• C often doesn't seem to matter (birth weight is an exception, type of religion is also an exception)
• E are always important (moderate effect)

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Part Two:  Gene Environment Interaction

Gene environment interaction:  The magnitude of the genetic effect depends on the environment.  Certain inherited genes are a "vulnerability", but they are only trigger a particular behavior if the person with the vulnerable gene also interacts with a particular type of environment. Here are some examples:

Aggression:  do genetic factors influence level of aggression?
 - If reared in a nurturing, protective home, then NO.
 - If reared in a chaotic, dysfunctional home, then YES.

Depression:  Is there gene environment interaction for depression?
- Depression is heritable and some of the genes for depression are not dependent on experiencing a certain environment.
- But, there are environmental influences that can influence the genetically based level of depression.
- Life stressors trigger the gene environment interaction for depression.
   - If you have low levels of life stress, then NO gene environment interaction.
   -  If you have high levels of life stress, then YES gene environment interaction.

IQ is an example of when there is NOT a gene environment interaction.
- Genes are important to IQ and environment is also important to IQ.
- But there are no genes which influence IQ that are triggered (or not) by experiencing a particular environment.

Why is gene-environment interaction important?
- In gene environment interaction, there are (potentially) two different points where you can intervene to help with problematic phenotypes.
– If you know that someone has an "at risk" gene, you can do environmental interventions to stop the vulnerable gene from being triggered - ie, Increase family cohesion in those at risk for aggression
– If you know that something is caused by a gene (as well as triggered by environment), then there is the possibility of pharmaceutical treatments.