2015 Keynote for The Clinical Genome Conference

@GenomeNathan #TCGC15

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‘Uncommon nonsense […] I should like to have it explained.’

- The Mock Turtle Alice’s Adventures in Wonderland (Dodgson 1865)

CHR07 : 1 079 1 5 506G/T

DLD G130C

CHR12 : 1 20737094C/T

ACADS R 107C

CHR04 : 88 1 1 8 244A/G

ABCG2 R236X

Chr12 : 1 0 27 1087C/C

CLEC7A Y238X


Nathan Pearson, PhD Senior Director, Scienti f ic Engagement & Outreach [email protected]

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)



Caraway Spearmint


7

N 14.007

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/r r/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. @GenomeNathan #TCGC15

Takehomes

Kanpai!

2015 Keynote for The Clinical Genome Conference

Health & Medicine

Transcript of 2015 Keynote for The Clinical Genome Conference