Personalized GenomicsOverview

• Genetic testing status and prospects• Types of human variation• Detection of human genomic variation• GWAS• Nextgen sequencing• Challenges• Ethical questions

Types of Genetic TestingTypes of Genetic Testing• Scientific Research

– Between species: phylogenetics– Within human species

• Medical– Diagnostic, predictive, carrier, prenatal, newborn

• Identification: DNA Fingerprinting– Military/large scale disasters

• Identification of remains– Paternity– Forensic

• Criminal investigations• DNA Databases: UK; USA• Exoneration of wrongfully convicted

• Scientific Research– Between species: phylogenetics– Within human species

• Medical– Diagnostic, predictive, carrier, prenatal, newborn

• Identification: DNA Fingerprinting– Military/large scale disasters

• Identification of remains– Paternity– Forensic

• Criminal investigations• DNA Databases: UK; USA• Exoneration of wrongfully convicted

Genetic Testing: ConcernsGenetic Testing: Concerns

• Uncertainties surrounding test interpretation

-The tests give only a probability for developing the disorder

• Lack of available medical options for some of these diseases

• The tests' potential for provoking anxiety; family issues

• Risks for discrimination and social stigmatization

-Legislative progress: GINA

• Uncertainties surrounding test interpretation

-The tests give only a probability for developing the disorder

• Lack of available medical options for some of these diseases

• The tests' potential for provoking anxiety; family issues

• Risks for discrimination and social stigmatization

-Legislative progress: GINA

GINAGINA• Genetic Information Non-discrimination Act:

Passed into law May 2008• Prohibits group health plans and health

insurers from denying coverage to a healthy individual or charging that person higher premiums based solely on a genetic predisposition to developing a disease in the future

• Bars employers from using individuals’ genetic information when making hiring, firing, job placement, or promotion decisions

• Genetic Information Non-discrimination Act: Passed into law May 2008

• Prohibits group health plans and health insurers from denying coverage to a healthy individual or charging that person higher premiums based solely on a genetic predisposition to developing a disease in the future

• Bars employers from using individuals’ genetic information when making hiring, firing, job placement, or promotion decisions

Nature Genetics

Genetic research on specific human

populations

Genetic research on specific human

populations

• deCODE model• Uses DNA from

over 100,000 Icelandic people

• Medical/genealogical records date back to 1,000 years ago

• Extensive informed consent/privacy measures implemented

• deCODE model• Uses DNA from

over 100,000 Icelandic people

• Medical/genealogical records date back to 1,000 years ago

• Extensive informed consent/privacy measures implemented

Process of IVF

1. Hyper ovulation

2. Egg Retrieval

3. Artificial Insemination

4. Embryo Transfer

                                                                             

Pre-implantation Genetic Diagnosis (PGD):

Genetic testing performed prior to embryo transfer

“The debate [around PGD] has been building since the late 1980s, when doctors at London's Hammersmith Hospital learned how to tease a cell from a 3-day-old embryo and study its chromosomes for gender.”

(Zitner 2002)

•Adds $2000 to IVF

•Reduces rate of miscarriages from 23% to 10%

•Does not increase chance of pregnancy

Preimplantation Genetic Diagnosis (PGD)

Preimplantation Genetic Diagnosis (PGD)

• Gender selection• Prenatal genetic diagnosis

-Spinal muscular atrophy (deletions in SMA gene)-Huntington’s Disease-CF: mutations that represent 75% of known CF mutations-Chromosomal translocations (single cell FISH)

• Future: fetal genome sequencing???• IVF & PGD

- selection of bone marrow matched offspring (Nash family)- other medical/non-medical uses

• Gender selection• Prenatal genetic diagnosis

-Spinal muscular atrophy (deletions in SMA gene)-Huntington’s Disease-CF: mutations that represent 75% of known CF mutations-Chromosomal translocations (single cell FISH)

• Future: fetal genome sequencing???• IVF & PGD

- selection of bone marrow matched offspring (Nash family)- other medical/non-medical uses

PGD for Family Balancing*Preimplantation Genetic Diagnosis (PGD) may be used to obtain cells for genetic analysis from embryos created by in vitro fertilization (IVF). GIVF offers PGD for gender selection for the purpose of family balancing for couples that meet qualifying criteria. Initial qualifications are: 

•Couple is married •Have at least one child •Desire a child of the less represented sex of children in the family

*italics added

PGD for Family Balancing*Preimplantation Genetic Diagnosis (PGD) may be used to obtain cells for genetic analysis from embryos created by in vitro fertilization (IVF). GIVF offers PGD for gender selection for the purpose of family balancing for couples that meet qualifying criteria. Initial qualifications are: 

•Couple is married •Have at least one child •Desire a child of the less represented sex of children in the family

*italics added

(taken from Genetics and IVF Institute Website)(taken from Genetics and IVF Institute Website)

DNA Testing for Forensics Applications• CODIS (Combined DNA Index System)• Evidence for guilt

• new: involvement of relatives• Evidence for innocence

•Innocence Project (>200 exonerations)

Genomic variation & their effects

Genomic variation & their effects

• Single gene defects (rare)- e.g., CF, Huntington’s

• Multigenic diseases (more common)- e.g., diabetes, heart disease, schizophrenia

• Non-disease conditions (all)- enhancements: immune system, cognition, physical ability, appearance

• Single gene defects (rare)- e.g., CF, Huntington’s

• Multigenic diseases (more common)- e.g., diabetes, heart disease, schizophrenia

• Non-disease conditions (all)- enhancements: immune system, cognition, physical ability, appearance

Direct-to-Consumer Marketing

Direct-to-Consumer Marketing

• Companies:– Use of genetic profiling to “guide”

diet/lifestyle– Lack of regulation

• Research:– Direct web-based solicitation of volunteers

with specific diseases/traits– Avoidance of red-tape; greater scope

• Companies:– Use of genetic profiling to “guide”

diet/lifestyle– Lack of regulation

• Research:– Direct web-based solicitation of volunteers

with specific diseases/traits– Avoidance of red-tape; greater scope

GAO 'Sting' 'Doesn't Bode Well' for DTC Industry

• July 23, 2010 • The United States Government Accountability Office dealt a

blow to several direct-to-consumer genetic testing firms • Issued a 33-page report outlining the group's investigation of

the "deceptive" marketing claims made by four DTC firms.• GAO team sent 10 saliva samples to each of the four

companies — not named in the report — from volunteer donors, and submitted along with them both accurate and fictitious health information.

• The GAO team received "test results that are misleading and of little or no practical use," and found "10 egregious examples of deceptive marketing– including claims made by four companies that “a

consumer’s DNA could be used to create personalized supplement to cure diseases," according to the report

– A customer service representative at one of the companies told a GAO volunteer that "an above average risk prediction for breast cancer meant she was 'in the high risk of pretty much getting' the disease."

Personal Genomics: Current Status & Prospects

Personal Genomics: Current Status & Prospects

• Sequencing cost and speed: – Nextgen sequencing: advantages & limitations– Strong motivation ($$) to get even better

• Personal Genome Project (PGP): George Church– “Public availability” experiment– See book: “Here is a human being” Misha Angrist– Privacy issues:Can DNA really be “deidentified”?

• 1000 Genomes Project– Genome sequences from different human

populations: HapMap Phase II

• Sequencing cost and speed: – Nextgen sequencing: advantages & limitations– Strong motivation ($$) to get even better

• Personal Genome Project (PGP): George Church– “Public availability” experiment– See book: “Here is a human being” Misha Angrist– Privacy issues:Can DNA really be “deidentified”?

• 1000 Genomes Project– Genome sequences from different human

populations: HapMap Phase II

Personal account of personal genomics

Studies on human height• Heritability of height is 0.8

– (80% of variation in height is due to genetic factors)

• 3 GWAS studies genotyped 63,000 individuals at 500,000 loci (biggest cohort analyzed to date)

• 54 loci explain ~4% of the variance. – What explains the remaining

96%?

Lessons from GWAS for understanding common traits or

diseases• Chip-based, not sequencing-based• GWAS only analyzes common known variants

(that you put on the chip)• Lander: Some regions of the genome are not

“HapMap-able”– i.e. cannot be typed by SNP technology

• Consequence: potentially important genomic regions are unexamined– Also a problem for current sequencing

technology

What have GWAS studies found?• Mostly low associations of common SNPs with

diseases/traits– Height = 80-90% genetic GWAS explains <5%– Autism = 90% genetic GWAS explains <5%

• GWAS studies have found significant associations, with over 400 genes IDed from different studies– But cumulative effects of all these explain very little

phenotype variation

• Two options: GWAS missed them or they are not there

GWAS LimitationsMissing Heritability & Strategies for Finding the Underlying Causes of Complex Disease

Nat Rev Gen 2010 – Eichler, et al

The Case of the Missing Heritability

Nature 2008 – Brendan Maher

Genetic Mapping in Human Disease

Science 2009 – Altschuler, Daly, Lander

G

One Possible Explanation: Non-SNP Variants Important

• GWAS ignored all but SNPs – no structural or copy-number variants (CNVs):– Detection of CNVs using SNP arrays is very

limited

• These have been shown important in schizophrenia, autism, microcephaly, heart disease…many more.

• Also, we know major genome differences between humans (even monozygotic twins)

• Good evidence that these regions are very dynamic, i.e. non-Mendelian

The 1,000 Genomes Project• Currently being sequenced using 35-mer illumina

reads• If you get a rare variant, may not be able to map the

read to the genome- “Reference genome” vs “de novo” assembly

• Structural/CNVs –very unlikely to catch much of these. Difficult to ID these with 35-mers…

• Strategy being explored: Read-depth proportional to copy number (e.g. MrFast; SUNs)

• Helped by long-read sequencing: e.g PacBio• May only be good at catching rare SNPs or structural

variants that are small (maybe 10 or less bp)

Structural variations among human genomes

DUF1220/NBPF Sequences & Recurrent Disease-associated 1q21.1 CNVs

A Walk Through Our GenomeA Walk Through Our Genome

--All regions of the genome are not created --All regions of the genome are not created equalequal--All regions of the genome are not created --All regions of the genome are not created equalequal

“Good genes & bad genes”: the value of a gene/allele is context-dependent“Good genes & bad genes”: the value of a gene/allele is context-dependent

• Effect on the individual-extensive/some/no knowledge

• Genetic background of the individual-between 2 individuals, 1 change every 1,000 bp -99.9% identical = 3 million DNA differences

• Environment -geographic (e.g. malarial region or not)-social issues (culture, customs, laws)-medical (status of non-genetic interventions

e.g., PKU vs. HD) • Effect on the species

-homogeneity vs. diversity

• Effect on the individual-extensive/some/no knowledge

• Genetic background of the individual-between 2 individuals, 1 change every 1,000 bp -99.9% identical = 3 million DNA differences

• Environment -geographic (e.g. malarial region or not)-social issues (culture, customs, laws)-medical (status of non-genetic interventions

e.g., PKU vs. HD) • Effect on the species

-homogeneity vs. diversity

Good genes and bad genes (cont.)Good genes and bad genes (cont.)

• Example of a good gene:- the globin gene variant that, when

heterozygous, protects against malaria

• Example of a bad gene: -the globin gene variant that, when

homozygous, produces sickle-cell anemia

-they are the same gene!

• Example of a good gene:- the globin gene variant that, when

heterozygous, protects against malaria

• Example of a bad gene: -the globin gene variant that, when

homozygous, produces sickle-cell anemia

-they are the same gene!

Coming DNA AttractionsComing DNA Attractions• The $1,000 genome

– “Personalized Medicine”– Reading your own genome

• Tracing the evolution of the human genome– “Evolutionary Genomics”

What genes made us human?– “Evolutionary Neurogenomics”

What are the genomic changes that underlie the evolutionarily unique capacities of the human brain?

-New way to study human brain function

• Many, many, many more A’s, C’s, G’s and T’s

• The $1,000 genome– “Personalized Medicine”– Reading your own genome

• Tracing the evolution of the human genome– “Evolutionary Genomics”

What genes made us human?– “Evolutionary Neurogenomics”

What are the genomic changes that underlie the evolutionarily unique capacities of the human brain?

-New way to study human brain function

• Many, many, many more A’s, C’s, G’s and T’s

Graduate Studies in Evolutionary Genomics?

Graduate Studies in Evolutionary Genomics?

• “It's money and adventure and fame. It's the thrill of a lifetime”– Carl Denham from “King Kong”

(1933)

• “It's money and adventure and fame. It's the thrill of a lifetime”– Carl Denham from “King Kong”

(1933)

                                                                   

King Kong (1933)