This text is meant to serve as concise outline of the project,
describing background, aims of the project, the obstacles,
current status, and history.
Healthy Genomes. Outline of the project.
Emanuel Yakobson, Thomas Bettecken, Edward N. Trifonov
Contents
Current campaigning group
Directorate
Sympathizers, involved in various ways
The aim of the project
Ethnic dimension
Lack of proper standard genome. Novelty
Genomic signatures of hereditary diseases
Stages of the project
Stage 1
Technical aspects and difficulties
Complete genomes available
References
Current campaigning group
Directorate
Emanuel Yakobson
Professor of Latvian University.
Molecular genetic studies. Racial differences in melanoma
and obesity.
emanuel.yakobson@gmail.com
1
Edward N. Trifonov
Professor, University of Haifa and
Masaryk University (Czechia). Molecular biophysics.
Genetic codes. Genome origin and evolution.
trifonov@research.haifa.ac.il
Indrikis Muiznieks
Professor, Prorector of Latvian
University. Molecular Biology, Nucleic Acids Research.
indrikis.muiznieks@lu.lv
Thomas Bettecken
Doctor of Medicine, MPI for
Psychiatry, Muenchen. Medical Genetics, Genotyping, DNA
sequencing. Chromatin structure.
bettecken@mpipsykl.mpg.de
Sergejs Zinovatnijs
Board Member of Latvian Sport Club
Maccabi. Business promotion, Jewish life in Latvia.
sergejs.zinovatnijs@maccabi.lv
Sympathizers, involved in various ways
Jon Entine
Science writer.
Genetics.
Author of
“Abrahams Children”
Zakharia Frenkel
bioinformatician, University of Haifa.
zfrenkel@yahoo.com
Janis Klovins
Genome Database of Latvian Population.
Biobanking, GPCR signaling, Human
Genetics, Type 2 Diabetes, Acromegaly
klovins@biomed.lu.lv
Abraham Korol
Professor. Director of Institute of
Evolution, University of Haifa.
Molecular evolution, recombination.
korol@research.haifa.ac.il
Eugene Levich
Professor, physics, computer science,
business promotion
eugenelevich@gmail.com
Paul Pumpens
Professor, Scientific Director,
Latvian Biomedical Research and Study
Center. Drug research.
2
paul@biomed.lu.lv
The aim of the project
Any two complete individual genome sequences, ~3*109 bases
each, are largely identical, except for a few million point
changes and other differences (2, 23). Total number of known
genetic variants is estimated as tens of millions (34, 35,
45). There is a whole spectrum of various types of differences
(41, 45) which include single nucleotide polymorphisms (SNPs),
deletions, insertions, as well as inversions (17),
translocations, variations in copy numbers of genes (4) and
repeats (26). These differences reflect ethnicity and ancestry
of the individuals, pathological patterns, as well as
individual “healthy” phenotypic traits.
The main idea of the project is to derive from existing
and forthcoming individual genome sequences a consensus, an
invariable part, without the individual changes, to serve as
standard for molecular medical and other studies. Many of the
individual variations are associated with various inherited
pathological conditions, from mild predisposition to serious
life threatening pathologies. Most of these, fortunately, are
recessive, but a chance to become dominant in progeny makes
them all highly undesirable. This connection of the changes
with genetic diseases and dispositions suggests a natural term
for the genome sequence consensus – Healthy Genome, since such
genome would not contain any of those variations, both
innocent and pathological ones. Master Genome, Consensus
Genome, Genome Standard, Universal Reference Genome, PanGenome would be possible synonyms of the Healthy Genome.
Thus, the aim of the project is to construct the
consensus Healthy Human Genome with the primary purpose of
having a balanced standard for medical genetic studies.
3
“A reference genome sequence is clearly needed for
research. Without a point of reference and common coordinate,
or naming system, research and clinical assay results cannot
be reported in ways that allow for inter-lab comparisons and
independent validation of research results.
... A basic coordinate system needs to be developed that can
accommodate any indel and rearrangements” (34).
Ethnic dimension
Ethnic variations of sequence polymorphisms are well
documented (13,14,16-20,24,27,45). A whole new discipline,
pharmacogenomics, is developing, based on different
susceptibilities of various ethnicities to drugs, as also
reflected in the differential occurrence of disease-associated
SNPs (19,20). Many genetic abnormalities are known which are
typical of specific ethnic or geographic groups (6,39,40). To
name a few: Tay-Sachs syndrome characteristic of Ashkenazi
Jewish population (7), cystic fibrosis of Caucasians,
especially amongst Danes (8), diabetes of Puerto-Ricans (1),
and hypoglycemia of Faroe Islands (38). The specific ethnic
SNPs spread from the geographic location of the respective
ethnic group (21) but their local higher occurrence persists.
“There are demonstrated differences in people’s genetic makeup
that predisposes some groups to different diseases based
solely on their ethnicity” (31). Thus, there are all reasons
to expect that the healthy consensus genome sequences derived
for specific ethnical groups would contain sequence features,
of ethnical pathology (and normality), different from
respective general Healthy Genome consensus (2). In other
words, in order to study one or another ethnically linked
genetic abnormality, one has to have separate genome standards
for respective ethnical groups – like Jewish Healthy Genome,
or Danish Healthy Genome, etc. These, of course, will be very
4
close to the general standard, though, perhaps, carrying quite
a few of ethnically specific differences (2, 32, 45). This
implies that for reliable detection and characterization of
the differences one has to have an unbiased general consensus
for Homo sapiens where many genome sequences of, desirably,
all major distinct ethnical groups would be equally presented.
These would be, first of all, Han (China), Bengalis
(Bangladesh), Germans, Russians, Italians, Yamamoto (Japan),
Punjabi (Pakistan), French, English, Mestizos (Mexico),…
Yoruba (Nigeria) etc., in descending order by population size
(e.g., as listed in (3)). The truly representative unbiased
consensus genome may be derived only by sequence analysis at
all consecutive stages of the construction of the consensus.
For example, the white race or mongoloid Han and Yamamoto
genomes may show some distinct common features, so that
additional care to avoid the biases in general consensus would
be needed.
The construction of the Healthy Genomes for various
ethnic groups is well justified. It will be only fair if every
ethnicity will be treated with equal medical attention, taking
into account all the differences, on the basis of very latest
achievements in genome studies.
Lack of proper standard genomes. Novelty.
Today of the order of 500-1000 genomes of various healthy and
sick individuals are available, at various stages of
completion. About 70 of them up to now may qualify as complete
fully assembled and mapped genomes (42, and listed below)
suitable for the derivation of the standard. Notably, the
individual sperm genomes (25) are not good for the task since
each one of them underwent multiple natural recombinations,
and their fertility (and normalcy) status is uncertain. Each
5
one of the above 70 or so can be used, of course, as
(temporary) reference for analyzing differences between
genomes (2), especially those which are associated with
genetic diseases. However, differences between individual
genomes do not fully reflect those between the genomes and the
(non-existing) standard. Currently, apart from few individual
personal genomes (e.g., of C. Venter and of J. Watson) the
most frequently used standard is the NCBI human reference
genome (11) which is derived from DNA samples of a small
number of anonymous donors (12). Comparisons of individual
Chinese, Korean and Yoruba genomes with the NCBI standard
reveals hundreds of thousands of differences common for these
three individuals (2). It appears that these common sites
rather represent the (non-existing) standard, while the NCBI
is an outlier.
Potentially, the sequences from 1000 Genomes project (10,
45) could be used for derivation of the standard. This
collection, however, is not intended to be ethnically
balanced, rather being geared to best overlap with available
databases of SNPs. For example, its sample list consists of
genomes of only 4 races (Whites, Blacks, Amerindians and East
Asians). It does not even include representatives of the
second largest ethnical group in the world, Bengalis (3).
Moreover, since most of the efforts of the Genome sequencing
projects are geared to the desirably complete collection of
SNPs and other structural variants, this task, too, suffers
from lack of good standard: “The current reference sequence,
being based on a limited number of samples, neither adequately
represents the full range of human diversity, nor is
complete”(34). Also, from recent account of the 1000 genomes
team: “the interpretation of rare variants in individuals with
a particular disease should be within the context of the local
(either geographic or ancestry-based) genetic background,”
(45) – alluding to the ethnical (geographic) genome standards.
6
Very much in line with our proposal, one could imagine sort of
logo, consensus genome: “If the Human Genomes sequence was
portrayed in this way, we might replace our arbitrary typespecimen with more natural, biologically accurate”(44).
Thus, no systematic effort to construct a balanced genome
standard of Homo sapiens has been attempted so far. The
novelty of the project is in its very target – the Healthy
Genomes standards.
Genomic signatures of hereditary diseases
There are over 9000 known genetic disorders and diseases.
Although rather detailed haplotypes for many of these diseases
are known today, the full genomic sequence characterization of
the diseases is not available, and realization is growing that
such full characterization is vitally needed (29). “That there
is currently no comprehensive, accurate, and openly accessible
database of human disease-causing mutations "is the single
greatest failure of modern human genetics," Massachusetts
General Hospital's Daniel MacArthur says” (as cited in 29). It
is also clear that any such standard can be developed only
after the Healthy Genomes will become available.
The genomic disease standards can be derived in the way
similar to ethnic genome standards. The consensus of many
individual genomes of the carriers of the disease has to be
compared with the Healthy Genome. The differences revealed may
then serve as the genomic signature of the disease, for
further studies and analyses. The personalized complete lists
of the abnormalities of individual patients, compared with
standards, will serve as a guide for preventive treatments,
and genetic consultations.
7
Stages of the project
1. Derivation of the general Healthy Genome standard.
Initial effort will include 10-15 available genomes. No
necessity to sample and sequence the individual genomes
at this stage. The exponentially growing number of
available sequenced genomes will be sufficient for
derivation of the Healthy Genome standard to any level
of completeness.
2. Ethnical genome standards
Jewish and Latvian genomes, perhaps, will be the first
to work on within the framework of the project, by
collecting blood samples, subcontracting genome
sequencing centers (at a cost ~$1000 or less per
genome) and constructing the ethnic standards. A large
collection of Latvian samples is already created at
Biomedical Research and Study Centre, University of
Latvia. Constructions of Korean and Chinese genome
standards are in progress in respective countries. Many
nations are likely to follow these examples soon. E.g.,
human genome variation map of the major ethnic groups
in Malaysia is under construction (30). Similar effort
in Singapore is on the way (33). And, again, all these
national genome standards will make sense only in
comparison with the general Homo sapiens genome
standard.
3. Genomic signatures of hereditary diseases.
The pathological genomic structural differences
specific for Jewish populations (like Tay-Sachs,
diabetes and others) will be major focus. With the
expected progress of the project and evaluation of
possible diseases and anomalies specific or most
problematic for Latvians, respective disease genomic
standards will be taken care of as well.
8
4. Ethnical and medical characterization of individual
genomes.
This will become possible after the general Healthy
Genome standard, Ethnical Healthy Genomes, and the
signatures of pathologies will be derived. Potentially,
these products of the project may become a major set of
Genome Standards of high demand. Every nation and every
ethnical group would need these standards for highest
efficiency of medicare and personal medicine.
The genomic standards are needed as well in studies on
human genomic history and evolution (e.g. 36,37), forensic
analyses, legacy cases. One can envisage also analysis and
prospective use of genomic sequence signatures of specific
talents and professional inclinations. The quick progress in
the whole genome studies and applications makes it rather hard
to predict the future developments. It is clear, however, that
all these developments will require a whole spectrum of
various genome sequence standards, starting with the Healthy
Genome of Homo sapiens.
Stage 1
For derivation of the initial first version of the Healthy
Genome 10-20 suitable complete genome sequences will be
selected from the list of currently available individual
genomes (below), keeping with the rule “largest ethnical
groups first”. Further additions would include more
ethnicities, in the order of appearance of the new suitable
sequences in publicly available sources.
The first and subsequent versions of the Healthy Genome
will be offered as commercialized product to various users for
a price to be then established, together with a package of
programs and instructions for use. The package will include
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the procedure of comparison of any genome of interest with the
standard, as well as listing and categorization of the
differences.
Technical aspects and difficulties
Derivation of the standard genomes and signatures is as
formidable as an important task. Technically, this is a
multiple alignment problem. The task is to align selected
subsets of the sequenced genomes to each other and to derive
the reference genomes, or standard hereditary disease
signatures, all products of the multiple alignments. Major
difficulties would be incompleteness of some of the genomes,
sequencing and mapping errors, multiple locations of the same
or almost identical genes, numerous tandem repeats with
variable copy numbers, sequence inversions, variable copy
numbers of genes (4) and possible other hurdles which may
appear in forthcoming studies of genome structure. The
construction of the reference genome has never been attempted
so far, and one may expect many surprises.
A package of computer programs has to be developed, to
build the standard genome from any number of individual
genomes, to compare any given genome with the standard, to
derive complete lists of differences (signatures) for the
individual genomes, to cluster the genomes with similar
signatures and to develop specific full signatures for various
genetic diseases. Some of the programs with similar functions
are publicly available and routinely used in the genomic
community (2,9).
Complete genomes available (refs as indicated and in Google)
10
HuRef – C. Venter
J. Watson
G. Church
NA18507 – Yoruba
Desmond Tutu Bantu (24)
!Gubi Khoisan (24)
Seong-Jin Kim SJK – Korean (2)
AK1 - Korean
YH – Chinese
Gordon Moore
Stephen Quake
works on sperm genomes
Marjolein Kriek
Hermann Hauser
14 others sequenced by Complete Genomics,
Unknown number sequenced by Knome,
7 genomes sequenced at high depth by the 1000 Genomes Project
(28):
Han Chinese South (CHS)
African Caribbean in Barbados (ACB)
Puerto Rican in Puerto Rico (PUR)
Peruvian in Lima, Peru (PEL)
Punjabi in Lahore, Pakistan (PJL)
Sri Lankan Tamil in the UK (STU)
Indian Telegu in the UK (ITU)
10 genomes from various labs (23) (10 more – from sick
individuals)
20 Korean genomes (27)
Steve Jobs (43)
First Irish Genome
Sitting Bull (Chief)
First Russian Genome (NCBI)
Glenn Close
Five Southern African Genomes (with Tutu)
(to be continued)
References
1. National Diabetes Information Clearinghouse. National
Diabetes Statistics, 2011. USA
2. Ahn S.-M. et al. (2009). The first Korean genome sequence
and analysis: Full genome sequencing for a socio-ethnic
group. Genome Res. 19(9): 1622–1629
3. CIA, The World Factbook.
11
4. Li J. et al. (2009). Whole Genome Distribution and Ethnic
Differentiation of Copy Number Variation in Caucasian and
Asian Populations. PLoS ONE 4(11): e7958
5. Macrae F., 12 July 2012. Gene test could soon see if future
lovers are compatible.
http://www.dailymail.co.uk/health/article-2172870/Genetest-soon-future-lovers-compatible.html?ito=feeds-newsxml
6. Milunsky A. Ethnicity and Genes.
http://www.babyzone.com/pregnancy/fetal_development/geneti
cs_gender/article/ethnicity-genes-disease
7. Sachs, Bernard (1887), "On arrested cerebral development
with special reference to cortical pathology", Journal of
Nervous Mental Disease 14 (9): 541–554
8. Wennberg C, Kucinskas V (1994). "Low frequency of the delta
F508 mutation in Finno-Ugrian and Baltic populations".
Hum. Hered. 44 (3): 169–71.
9. Axelrod N. et al. The HuRef Browser: a web resource for
individual human genomics. Nucleic Acids Res. 2009
January; 37(Database issue): D1018–D1024.
10. G Spencer, International Consortium Announces the 1000
Genomes Project, EMBARGOED (2008)
http://www.1000genomes.org/files/1000GenomesNewsRelease.pdf
11. Pruitt KD, Tatusova T, Maglott DR (2007) NCBI reference
sequences (RefSeq): a curated non-redundant sequence
database of genomes, transcripts and proteins. Nucleic
Acids Res 35: D61–65
12. PlOS Genetics,
Sept. 2011, Dewey FE, Phased Whole-Genome
Genetic Risk in a Family Quartet Using a Major Allele
Reference Sequence.
13. Mori M., et al. Journal of Human Genetics (2005) 50, 264–
266. Ethnic differences in allele frequency of autoimmunedisease-associated SNPs
12
14. Silverberg MS, et al. European Journal of Human Genetics
(2007) 15, 328–335. Refined genomic localization and
ethnic differences observed for the IBD5 association with
Crohn's disease
15. Human Genome Project Opens the Door to Ethnically Specific
Bioweapons. Project Censored.Apr. 30, 2010.(web source)
16. Ghodke Y. et al. Profiling single nucleotide polymorphisms
(SNPs) across intracellular folate metabolic pathway in
healthy Indians.
Indian J Med Res 133, March 2011, pp
274-279
17. Karyn Meltz Steinberg et al., Structural diversity and
African origin of the 17q21.31 inversion polymorphism
Nature Genetics. Published online: 01 July 2012
18. Richard S Spielman et al. Common genetic variants account
for differences in gene expression among ethnic groups
Nature Genetics 39, 226-231, 2007
19. Kimchi-Sarfaty C. et al., Ethnicity-related polymorphisms
and haplotypes in the human ABCB1 gene. Pharmacogenomics.
2007 Jan;8(1):29-39.
20. Peter H. O’Donnell1 and M. Eileen Dolan. Cancer
Pharmacoethnicity: Ethnic Differences in Susceptibility to
the Effects of Chemotherapy. Clin Cancer Res. 2009 August
1; 15(15): 4806–4814.
21. Templeton A.
www.faculty.biol.ttu.edu/strauss/Phylogenetics/Readings/Te
mpleton1998
22. Hunt, S. (2008) Pharmacogenetics, personalized medicine,
and race. Nature Education 1(1)
23. Pelak K, Shianna KV, Ge D, Maia JM, Zhu M, et al. (2010)
The Characterization of Twenty Sequenced Human Genomes.
PLoS Genet 6(9): e1001111
24. Stephan C. Schuster et al., Complete Khoisan and Bantu
genomes from southern Africa. Nature 463, 943-947; 2010
13
25. Jianbin Wang et al. Genome-wide Single-Cell Analysis of
Recombination Activity and De Novo Mutation Rates in Human
Sperm. Cell, Volume 150, Issue 2, 402-412, 20 July 2012
26. Trifonov, E. N., The tuning function of the tandemly
repeating sequences: molecular device for fast adaptation.
In: Evolutionary Theory and Processes: Modern Horizons,
Wasser, S. P. (Ed.), Kluwer Academic Publishers, pp 115138 (2004)
27. http://www.bio-itworld.com/2011/09/13/korean-genomeproject-finds-korea-SNPs.html
28. http://www.1000genomes.org/about
, 2012
29. http://www.genomeweb.com/mdx/quest-clarity?page=show (T.
Vance, A quest for clarity, July/August 2012)
30. http://1mhgvc.kk.usm.my/
31. http://www.examiner.com/article/ethnicity-specificreference-genome-improves-everyone-s-health; Dewey FE et
al. (2011) Phased Whole-Genome Genetic Risk in a Family
Quartet Using a Major Allele Reference Sequence. PLoS
Genet 7(9): e1002280
32. http://ethnicgenome.wordpress.com/
33. http://www.statgen.nus.edu.sg/~SGVP/
34. Rosenfeld JA, Mason CE, Smith TM (2012) Limitations of the
Human Reference Genome for Personalized Genomics. PLoS ONE
7(7): e40294
35. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, et al.
(2001) dbSNP: the NCBI database of genetic variation.
Nucleic acids research 29: 308–311
36. Rocca RA, Magoon G, Reynolds DF, Krahn T, Tilroe VO, et
al. (2012) Discovery of Western European R1b1a2 Y
Chromosome Variants in 1000 Genomes Project Data: An
Online Community Approach. PLoS ONE 7(7): e41634
37. Nature 485, Special issue: Peopling the planet. (03 May 2012)
38. Jef Akst, Island disease, The Scientist, August 2012.
39. Yakobson E et al. A single Mediterranean, possibly Jewish,
origin for the Val59Gly CDKN2A mutation in four
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melanomaprone families. EUROPEAN JOURNAL OF HUMAN
GENETICS 11,
288-296, 2003
40. Leachman SA,...Yakobson E, et al. Selection criteria for
genetic assessment of patients with familial melanoma.
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY 61, 677684, 2009
41. S. Levy,... C. Venter, PLoS Biol 5(10): e254. The Diploid
Genome Sequence of an Individual Human
42. http://www.completegenomics.com/news-events/pressreleases/Complete-Genomics-Adds-29-High-Coverage-CompleteHuman-Genome-Sequencing-Datasets-to-its-Public-GenomicRepository--119298369.html
43. Lohr, Steve (2011-10-20). "New Book Details Jobs's Fight
Against Cancer". The New York Times.
44. Weiss KM http://the-scientist.com/2012/08/17/opinion-whatis-the-human-genome/
45.
An integrated map of genetic variation from 1,092 human
genomes. The 1000 Genomes Project Consortium. Nature
491,56–65 (2012)
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Funding
The funding is expected from donations or from governmental
support. Currently the project has no support.
The Latvian group concentrates on possible stipend for
Ph. D. student, cosupervised by professors in Riga, and in
Haifa.
Another prospective support may come from a large
European grant (in progress, Latvian University).
All people involved have to increase the circle of
sympathizers, hoping to get eventually a sponsor or few.
Updated November 2, 2012.
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