Recent Advances in Human Genetics

The“New” vs. the“Old Genetics”

What is so new?

Why is this different?

Background

What is a gene?

A gene is a physical structure made from DNA. It carries the information that leads to the creation of a protein. Proteins are the building blocks of life.

The human genome, by the letters . . .

There are 4 letters in the genetic code (C, T, A, G) There are 3,000,000,000 letters in the human genome We know about 80% of these now; we’ll know the rest by 2003 There are as many as 140,000 genes in the human genome Most genes have 1000 - 5000 letters of ‘information’ spread

over 5000 - 500,000 letters We don’t understand the junk in-between Most diseases are caused by just one letter being wrong Two unrelated humans are different at about 3 million letters

The “Old Genetics”

Involves conditions wholly caused by

An extra or missing complete chromosome or part of a chromosome e.g., Down syndrome, Turner syndrome,

Cri-du-chat syndrome

A mutation in a single gene e.g., cystic fibrosis, Marfan syndrome,

Fragile-X syndrome, achondroplasia

Down’s SyndromeSome genetic disorders are caused by large chromosomal abnormalities, either structural or numeric. Predictive testing, including prenatal diagnosis, has been available for many years

The “Old Genetics”

These conditions

• Are relatively rare

• Range in severity, but most have a large impact on the individuals and families affected

• Exhibit patterns of inheritance, expression and penetrance that follow well-established ‘rules’

• Most persons are not affected, thus genetics has played a relatively minor role in health care (and in society)

Background

How are genes inherited?

Genes are passed from parent to child. Both parents give genes to each child. Inheritance follows typical patterns --

DominantRecessiveSex linkedMitochondrial

Dominant Inheritance

Recessive Inheritance

The “New Genetics”

Involves common conditions for which:

• An individual’s relative risk for the condition is directly modified by alteration(s) in gene(s)

• e.g., breast cancer, colon cancer, diabetes, atherosclerosis, Alzheimers disease, schizophrenia, mood disorders, others

• An individual’s RR for conditions associated with environmental or behavioral risk factors may be indirectly modified by variations in genes

• e.g., tobacco-related disease, HIV, obesity

The New Genetics: Nature vs. Nurture

Heredity

EnvironmentBreast Cancer

Colon Cancer

Diet

Smoking

Parity

BRCA 1/2

HNPCC

FAP

The “New Genetics”

These conditions:

• Range in severity but have a large impact on individuals and families who are affected

• Are very common--virtually everyone is directly affected

• Predict a much larger role for genetics in health care and society

Leading Causes of Death in Vermont, 1996

1 - Heart Disease

2 - Cancer

3 - Cerebrovascular disease

4 - COPD

5 - Injuries

6 - Influenza/Pneumonia

7 - Diabetes Mellitus

8 - Arterial disease

9 - Suicide

10 - Septicemia

Leading Causes of Death in Vermont, 1996

1 - Heart Disease

2 - Cancer

3 - Cerebrovascular disease

4 - COPD

5 - Injuries

6 - Influenza/Pneumonia

7 - Diabetes Mellitus

8 - Arterial disease

9 - Suicide

10 - Septicemia

Gene testing already in common use Genetic risk factors known but tests not yet in regular use

The “New Genetics”

• Is changing our understanding of both rare and common diseases

• Is changing the tools we have to predict, diagnose, and manage both rare and common diseases

Risk of Colorectal Cancer (CRC)

0 20 40 60 80 100

General Population

Personal history of colorectal neoplasia

Inflammatory bowel disease

FAP

HNPCC mutation

5%

15-20%

15-40%

70-80%

>95%

Lifetime risk (%)

The New Genetics and Common Diseases

Breast Cancer

70%

20%

10%

Sporadic ClustersHereditary

Ovarian Cancer

90%

10%

Sporadic Hereditary

The hereditary form of many common diseases is clinically similar to the nonhereditary form; these can be difficult to distinguish without DNA analysis.

Background

What is penetrance?

Penetrance is the fraction of persons carrying a deleterious gene that are affected by the disease. If all carriers are affected, penetrance is 100%.

Age Specific Penetrance

0

20

40

60

80

100

20 40 60 80

Affected withcolorectal cancer (%)

Percentage of individuals with an altered disease gene who develop the disease

HNPCCmutationcarriers

Age

Generalpopulation

The “New Genetics”

• Is changing our understanding of both rare and common diseases

• Is changing the tools we have to predict, diagnose, and manage both rare and common diseases

Familial Breast and Ovarian Cancer

•

•

•

•Breast CancerOvarian Cancer

•Fathers can be carriers

•Carriers can be unaffected

Background

What is a mutation, and how is this different from a polymorphism?

Mutations are changes in genes that were not present in a previous generation. In the jargon of genetic disease, mutations are deleterious.

Polymorphisms are like mutations, but are not deleterious.

Background

What is a founder effect?

Founder effect describes the observation that in some populations, a single form of a gene (or a mutation) is more prevalent than in other populations. These populations are less heterogeneous racially, ethnically, and culturally than some other populations due to common ancestry.

BRCA1: 185delAG

Normal:5’-AAAATCTTAGAGTGTCCCATCTG-3’Mutant:5’-AAAATCTTAGTGTCCCATCTGG

C T A G C T A G

One of 3 common founder mutations causing FBOC in the Ashkenazi Jewish population. Approximately 3% of persons of Ashkenazi descent carry one of these 3 cancer-predisposing mutations.

The “New Genetics”

• Is changing our understanding of both rare and common diseases

• Is changing the tools we have to predict, diagnose, and manage both rare and common diseases

The “New Genetics”

Will change health care by providing knowledge of individual disease predispositions, allowing

• Population-based (or clinic-based) risk stratification to identify those who will benefit the most from available interventions

• Individualized surveillance or ‘risk management’ programs tailored to an individual’s risk of disease (e.g. heart disease, mental illness, cancer, dementia)

The “New Genetics”

Will change health care through predictive ‘pharmacogenetics’

• Optimization of therapeutic or preventive medicines based on genetic factors

• Prediction and prevention of potential adverse outcomes, side effects, or unusual resposes to drugs cause by individual genetic variation (e.g., cancer therapeutics)

The New Genetics: PharmacogeneticsVincristine is commonly used to treat several forms of

cancer. A small subset of persons, and particularly those with hereditary neuropathies, may suffer severe and atypical neurological injuries from treatments involving vincristine.

In 1999, it was found that families with a certain genetic defect leading to Charcot-Marie-Tooth syndrome, the most common inherited neuropathy, affecting 150,000 in the US, had predictable and severe reactions to Vincristine.

The New Genetics: PharmacogeneticsThiopurine S-methyltransferase (TPMT) is an enzyme our

bodies use to detoxify certain substances, including drugs commonly used for chemotherapy. There are 8 common variant forms of this enzyme in humans.

In 1998, it was found that one genetic type that is less active is associated with 10-15X higher blood levels of the drug azathioprine than others. Persons carrying this type suffer severe hematopoietic toxicity from azathioprine at doses others tolerate well.

The “New Genetics”Will reveal an inherited genetic basis for

characteristics we do not see as “diseases” and that many do not see as innate

• Traits, e.g., height, intelligence

• Behavior, e.g., alcoholism, violence, sexual orientation

• Personality, e.g., happiness/sadness, confidence/anxiety, altruism/greed

Reported in Nature, August 1999

Transgenic mice that carry the Vasopressin Receptor gene from the prairie vole change their social behavior completely to be like that of the prairie vole

A study comparing smokers who had quit several times but still smoked with smokers who had successfully quit showed the a common genetic variant form of the dopamine receptor gene, DRD4, was much more common among the first group than the second. This association has now been reported for other addictive behaviors also.

1998, American Journal of Human Genetics

The New Genetics

The risks, benefits and unforseen consequences of rapidly developing genetic technologies are rarely obvious and require careful study

• Example: Are You My Father?

Background

What is a genetic marker?

A genetic marker is a ‘tag’ near or within a gene of interest. Genetic markers are usually highly polymorphic.

Microsatellite polymorphisms

…ctgaggtctagCACACACACACACACACAtgccagtg..

highly polymorphic region

•Repeat may be (2,3,4 bp)n; with n=10-50 or more•extremely common in the human genome•CA dinucleotide repeats are most common•highly polymorphic, with h>0.75 & high PIC values•methods to assay are quick, easy, and cheap

Parentage

• Paternity test kits are now available by mail, directly to the consumer

• Clinical DNA tests for inherited disorders often reveal nonpaternity, undisclosed adoption, or other family secrets that are irrelevant to the purpose of testing

Family 2724: DNA Test for inherited disease

•CM is a 7 m.o. female child born to healthy parents with no history of inherited disease. She has two older siblings. CM showed signs of developmental delay and moderate hypotonia in her first few months of life and was brought to her pediatrician for evaluation. Upon pediatric examination, she was found to have leukocoria of her left eye; MRI imaging also showed a paucity of central white matter and a thin corpus callosum.

• EUA revealed a 2cm retinoblastoma in her left eye with growth toward the macula.

•Cytogenetic testing revealed 46,X,t(X:13)(p?11.2:q12).

•DNA testing was requested to determine the likelihood of hereditary retinoblastoma.

RBi2 D2S147 D5S82D10S587

Family 2724: Conclusion

•DNA testing could be used to modify risk but was inconclusive for the purpose of confirming inherited disease due to nonpaternity.

•Because of the presence of nonpaternity, the test result was reported as ‘indeterminate’ and is not useful clinically.

Triplet repeat diseases

CGG CAG CTGGAA

AUG TAA

Gln

Fragile X Syndrome

FriedreichAtaxia

MyotonicDystrophy

Spinal & BulbarMuscular Atrophy

SpinocerebellarAtaxia Type I

Huntington Disease

Haw River Syndrome

Machado-Joseph Disease

Anticipation

The New Genetics

The risks, benefits and unforseen consequences of rapidly developing genetic technologies are rarely obvious and require careful study

• Example: Who was at fault for our child being born like this?

The New Genetics: Rapid Changes, Unforseen Implications Achondroplasia and FGFR3

Most children born with achondroplasia, the most common form of dwarfism, are born to parents of normal stature. Until 1997, the genetic basis for achondroplasia was unknown and DNA testing was impossible.

In 1997, genetics researchers discovered that a single nucleotide in the FGFR3 gene (nucleotide 1138, exon 10) was responsible for essentially ALL cases of achondroplasia.

The simple genetic basis for achondroplasia meant that easy, rapid, interpretable, and cheap ($200) DNA testing became available overnight.

In 1998, Wilkin et al. published that 40/40 new cases of achondroplasia were due to FGFR3 defects that arose on the father’s FGFR3 gene.

Background

What is a gene test?

A gene test involves the direct analysis of either a gene sequence (mutation or polymorphism) or a genetic marker.

How do we decide if a genetic test will be useful to predict carrier status for a disease or condition?

•Will the test improve the quality of care available to the carrier (e.g. through early detection, chemoprevention, or prophylaxis)?

•Will the DNA test improve this person’s quality of life?

•Will the test reduce the cost of caring for this person?

•Is knowledge of carrier status important to this person for reasons other than their health care (e.g. family planning, preventive behaviors)?

The New Genetics and Ancestry

Clinically relevant genetic variants are found with variable frequency in different populations (e.g. FBOC)

• Cultural, religious and ethnic factors are highly relevant to any discussion of genetic risks; likewise, to the perceptions of same

• The feasibility of carrier testing, population screening, and other interventions varies in different groups due to ‘founder effects’

New Genetics, Common Genes and Ancestry

1 in 31 persons of European extraction carry a single mutation (35delG) in Connexin-26, a gene that causes 49% of recessive nonsyndromic deafness. 1 in 25 persons of Ashkenazi descent carry a different mutation (165delT) in Connexin-26.

1 in 7 persons of Armenian, Turkish, Arabic, or Sephardic Jewish ancestry carry a gene defect for Familial Mediterranean Fever, a recessive disease leading to renal amyloidosis.

The New Genetics and Common Genes

1 in 10 persons carries one of 2 common mutations that cause 95% of hemochromatosis, an often undiagnosed recessive disorder leading to multi-organ damage from iron excess. 1 in 200 persons is affected in the U.S.

1 in 50 persons in the U.S. carries a dominant mutation in prothrombin (20210A), leading to 5-fold excess risk of thrombosis. 60% with this mutation also carry the Factor V Leiden gene mutation, further increasing risk of DVT, pulmonary embolism, stroke and MI.

1 in 38 persons of Ashkenazi descent carries one of 3 common mutations in BRCA 1 and BRCA2.