2015 Keynote for The Clinical Genome Conference

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@GenomeNathan #TCGC15

‘Uncommon nonsense […]
I should like to have it explained.’
- The Mock Turtle
Alice’s Adventures in Wonderland (Dodgson 1865)
CHR07:107915506G/T
DLD G130C
CHR12:120737094C/T
ACADS R107C
CHR04:88118244A/G
ABCG2 R236X
Chr12:10271087C/C
CLEC7A Y238X

Nathan Pearson, PhD
Senior Director, Scientific Engagement & Outreach
npearson@nygenome.org
Genomic sense, beyond uncommon nonsense

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Dodgson Darwin
Mendel de Chancourtois
TED(DeadWhiteMen) 1865?

Some chemistry history: the Telluric Helix

In 1865, we knew of 56 elements.
•  Simplest readily isolable kinds of stuff
•  de Chancourtois first catalogued by weight-periodic similarity
•  Properties key to understanding (and sensibly tinkering with) world
But we already knew & classified molecules.
•  Combos of 1+ elements, in particular amounts & linked configurations
•  Do more than sums of their constituent elements
•  Some (nicotine!) were already characterized & toxicologically tracked
You learned about both…
Some chemistry history: What about health?
in grade school.

Oregano
C10H14O: Sex, Drugs, Rock’n’roll

Rosemary

Thyme

Saffron

Pennyroyal
(abortigen??)

Headache tree
(puke-ogen!)

Beetle pheromone
(pest control)

CarawaySpearmint

7
N14.007
Harmless in diatomic free form
Neurotoxic in some alkaline
combos with C,H,O
How we don’t track the chemistry of health

How we don’t track the chemistry of health

How we do(!!) track the chemistry of health

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How to track the genomics of health?

How to track the genomics of health?
Conventionally, we classify and report variants.
•  Simplest reliably heritable way two chromosomes can differ
•  May match or mismatch arbitrary reference genome
•  Spellings & distribution say much about history & physiology
•  Tying to health presumes simple, strong effects
Rooted in early clinical genetics (reading few genes, in few people, mostly sick)
Sweeps impenetrance under vast rug
We should instead classify and report genotypes.
•  Combos of 1+ variant(s), at 1+ site(s), on 1+ chromosome(s)
•  Constituent variants may interact non-additively
•  Elastically track growing insights, starting w/today’s single-site knowledge
•  Mendel got this!


genomes chemistry
variant

element
rare penetrant polonium (harmful in any combo)
reference hydrogen (often implicit, to compress)
hyper-recurrent radionuclide (often made anew)
genotype
molecule
partial moiety
partial & informative functional group
zygosity/ploidy
stoichiometry

coinheritance bond
linked covalent
unlinked ionic
imprinting handedness
reproduction reaction
Mendel, meet Mendeleev

Non-additivity: We’ve known from the start…
R/R R/r
r/rr/R

Non-additivity: We’ve known from the start…
Dominance
So widespread & easily spotted, we specially named it.

XX/XY-dependence
So obvious, we’ve forgotten or footnoted it.
Other stably diverse local haplotypes
So easy or hard(!) to read & integrate, we’ve swept under special rugs.
•  mtDNA (health-informative) & MSY (less-so)
•  HLA_, IG_, other hypervariable, immunity-relevant segments
•  CYP_

More non-additivity: Same-gene, distinct sites
Compound-h___zygous etiology
‘Recessive’ variants at distinct sites in a gene turn each other dominant, &c.
•  Many examples (if hard to spot & validate!…)

Rare-genotype-associated health
Variant(s) buffer expected harm of nearby variant(s)
•  e.g., prion susceptibility/resistance in PRP1 (PMID26061765)

More non-additivity: Cross-gene
Rare-genotype-associated disease (digenic/&c. etiology)
‘Recessive’ variants in distinct genes turn each other dominant
•  e.g., RDS & ROM1 in retinitis pigmentosa (PMID8202715)
Rare-genotype-associated health
Variant(s) buffer expected effect of variant(s) in distinct gene(s)
•  e.g., APP & APOE-ε4 in Alzheimer risk (PMID22801501)

More non-additivity: Into the unknown…
Noisy penetrance, even in our best understood (ACMG56…) genes
Among men w/‘pathogenic’ variants in MSH2, from 224 families1
•   ~1/6 face >90% (family-wise estimated) lifetime colorectal cancer risk
but…
•  ~1/6 face < 10% lifetime risk(?!)
Why do we know so little?
•  Interactions – some likely genetic & non-additive? – will matter.
•  But we breed too slowly, with genomes too vast and habits too complex,
to easily spot such interactions in the wild.
1: PMID23255516

Streamlining care: Sip, then act.
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Streamlining care: Sip, then act.

‘Pathogenic’ variant (ClinVar) ! ! ! ! ! Outlook ! ! !!
!
chr17:043094569C/T! ! ! ! !personal risk (breast cancer)
chr11:002583535C/G! ! ! ! !personal risk (long QT syndrome)
chr19:011113382G/A! ! ! ! !personal risk (high LDL)
chr01:025611244T/T! ! ! ! !personal risk (hemolytic anemia)
chr11:005226778G/A! ! ! ! !personal risk (beta-thalassemia)!
!
Streamlining care: A genome, in variants

‘Pathogenic’ variant (ClinVar) ! ! ! !Outlook (high risk) !!
!
chr17:043094569C/T! ! ! ! ! ! !breast cancer
chr11:002583535C/G! ! ! ! ! ! !long QT syndrome
chr19:011113382G/A! ! ! ! ! ! !high LDL
chr01:025611244T/T! ! ! ! ! ! !hemolytic anemia
chr11:005226778G/A! ! ! ! ! ! !beta-thalassemia!
!
Streamlining care: A genome, in variants

Informative genotype ! ! !Outlook (high or modest/low risk) !
!
chr17:043094569C/T! ! ! ! ! ! !breast cancer
chr11:002583535C/G! ! ! ! ! ! !long QT syndrome!
chr19:011113382G/A! ! ! ! ! ! !high LDL
chr01:025611244T/T! ! ! ! ! ! !hemolytic anemia (family risk)
chr11:005226778G/A! ! ! ! ! ! !beta-thalassemia (family risk)!
!
!
Streamlining care: A genome, in 1-site genotypes

Informative genotype ! ! ! ! !Outlook (high or modest/low risk) !
chr05:096788627T/T chr06:031398010A/A! !ankylosing spondylitis1
chr17:043094569C/T chrX/Y! ! ! ! breast cancer (family risk)
chr11:002583535C/G chr11:002463573C/T! !long QT syndrome (family risk)2
chr19:011113382G/A chr11:005226778G/A !high LDL (family risk)3
chr01:025611244T/T! ! ! ! ! ! !hemolytic anemia (family risk)
chr11:005226778G/A! ! ! ! ! beta-thalassemia (family risk)!
!
!
Streamlining care: A genome, in full genotypes
1: PMID21743469
2: PMID23856471
3: PMID10634824

Genotypes...
abound, even more than variants.
•  But we need only track informative ones (as they slowly accrue)
•  Converting now, with ambiguity codes, would roughly double (still modest) ClinVar size
overlap each other.
•  So need structured syntax & schema
•  Tractable, even moreso in silico than on paper
each mark fairly few people.
•  Greatly hinders association stats(!) – but parallelized in vitro work may help a lot
•  Only track when cross-person health-informative
•  Privacy worry (hinders ClinVar/&c’s implementation) presumes widespread genome data
Variants…
form genotypes…and do help understand human history & physiology.
•  So still canonically catalog them
•  And still flag them within personal genotypes, when family health-informative
Twists

Clinically classifying informative genotypes would help
•  gird healthcare for narrow use of genomes today, broader use tomorrow.
•  ease caregivers’ jobs, by keeping genome reports short and clear.
•  lengthen lives, by most sharply conveying available insights.

Let’s switch before variant-limited thinking deeply pervades care.

What you can do
•  Bioinformatician? Structure data for multisite genotypes (even helps QC!).
•  Genomicist or sequencee? Share individuated genomes, to boost power.
•  Bench scientist? Help functionally assay genotypes in parallel.
•  Clinical geneticist? Think in – and report – genotypes.
•  Caregiver or patient? Think in – and request – genotypes.
And yes. Spread. The. Word.
Takehomes

2015 Keynote for The Clinical Genome Conference

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