What is it about humans that distinguishes us from the rest of the animal kingdom?  Is it our upright walking?  Our language?  Our love of Reality TV?  Even though we are said to be 99% genetically identical to our closest evolutionary relative, the chimpanzee, we clearly differ vastly from them physically and behaviorally.

For many years, scientists have attempted to understand how our species came to be so different from any other on the planet.  In the October issue of Nature Reviews Genetics, scientists at the UCLA and the Howard Hughes Medical Institute examine recent research to understand how genetic mutations have set us apart from our nearest relatives. In addition, they discuss how these genetic changes relate to the vast array of physical and behavioral differences that also have to be considered to fully understand what makes our species so unique.

The 1% Difference

The authors begin their examination of human uniqueness by focusing on the overall genetic differences between our species and chimpanzees.  Many years ago, research revealed that humans and chimpanzees are remarkably similar in terms of both genetic and biochemical structure.  Scientists hypothesized that because the two species are so structurally similar, the differences between humans and chimps would turn out to be primarily in the way that genes – and therefore proteins – are expressed.  Further analysis confirmed that there is only a 1% difference in overall genetic and biochemical structure between the two species — a number many people still cite today.

However, the authors argue that more recent analysis has actually shown that deletions and duplications of DNA in both species bring the genetic difference between the two to about 4% across the entire genome.  These and other findings have, according to the authors, “dashed the hope that it would be simple to determine the key genetic differences between humans and closest evolutionary relatives, that is, the genomic aspects of ‘what makes us human’ ”.

Yet many recent breakthroughs in comparative genomics have identified human genetic features that may be unique.  Below are two examples:

MYH16

One key difference between humans and chimpanzees is the difference in brain size.  Humans have an average brain volume of about 1500 cm³, which is roughly three times the size of a chimp’s.  While having a comparatively large brain was one of the most important factors in the evolution of our species, it has also resulted in an organ that is very expensive to maintain.  In fact, many anthropologists have argued that in order for our large brains to have evolved, there must have been a simultaneous reduction in the size of other organ systems and muscle mass.

In 2004, scientists discovered a gene, MYH16 that may have been involved in that trade-off between increased brain size and decreased muscle mass.  Believed to be related to the growth of muscles in the jaw of chimpanzees and other apes, MYH16 has been mutated in humans so it remains switched off.  Scientists hypothesize that the gene’s lack of expression in humans causes an eight-fold reduction in the size of muscle fibers in the human jaw.  Interestingly, the timing of this mutation appears to have happened about 2 million years ago, when Homo erectus – the first of our fossil ancestors to exhibit a significant increase in brain size, evolved in Africa.

FOXP2

Sometimes referred to as “the language gene,” FOXP2 made a splash in the popular media when it was first described in 2002, because a very slight mutation in the human version is believed by some to have led to the evolution of language in humans.

FOXP2 is not unique to humans.  In fact, many species – including songbirds and alligators – have the gene, which is required for proper brain development.  Though the human FOXP2 gene is slightly different, it has been found to be related to vocal learning in birds, and may even be tied to the evolution of echolocation in bats.

In addition, new research has suggested that it may not be the FOXP2 gene itself, but rather a related genetic pathway, and it is that related gene that may be involved in the evolution of speech and language development in humans.  At the moment the exact relationship between FOXP2 and human language remains unresolved — an illustration of the genome’s complexity.

Genotype vs. Phenotype

The authors conclude their review by proposing a method of examining human uniqueness from a genomic perspective in light of the fact that “traditional evolutionary biology approaches have yet to explain most of the unique features of humans.”  They argue that in order to move the field of evolutionary genomics forward, and to truly understand what it means to be ‘human,’ there must be more of an effort to connect changes at the genetic level (our genotype) to changes at the physical level (our phenotype).  Interestingly, questions of the relationship between genotype and phenotype form the cornerstone of 23andMe’s research arm, 23andWe.

Finally, the authors argue that it will take scientists from a variety of disciplines – developmental biology, genetics, anthropology, anatomy, sociology, and many others – to fully examine the myriad of ways in which humans are set apart from our closest relatives.  It is at this point, the authors conclude, that we will fully understand what it means to be ‘human.’

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Team 23andMe likes games – Wii tennis and Segway polo are big here. So are friendly wagers over a new employee’s ACTN3 genotype, or whether a given Markov Chain Monte Carlo simulation will converge during our lifetimes.

So in the spirit of friendly competition, we’re starting the 23andMe Win Your Genome Contest. The winner gets our Personal Genome Service™ for one person of his or her choice.

Everybody else gets to try again the next time, as we’re planning on holding a new contest every month or so (though we may skip a month from time to time).

The winner of our inaugural competition will be the person who can best describe Lilly Mendel, a real person whose genetic data can be seen with a free 23andMe demo account.

We don’t require you to include any particular characteristics, but obviously the major physical traits in Gene Journal (now called Health and Traits) (height, weight, eye color, etc.) are a good place to start.

Creative speculation is allowed and encouraged. Think you know where Lilly’s grandparents were born? Her favorite movie? Her sleeping habits? Anything goes, but you must justify every element of your description with some aspect of Lilly’s genetic data. So even if you think you know who Lilly is based on other lines of reasoning, you’ll still need a SNP and a convincing or at least amusing argument as to why you think it indicates an inordinate fondness for the Beatles.

Entries will be judged on an entirely subjective scale – the winner will be whichever description we consider the best based on accuracy, creativity and cleverness. The winner’s description will be revealed on this blog – but Lilly’s identity will not.

Send your entries to contest@23andme.com. The deadline is midnight Pacific time on Friday, May 9. One final note: We can accept entries only from United States residents who are 18 years of age and older.

Want to know every last detail? There’s a ton of fine print after the jump.

Photo from V2-Media/istockphoto

The 23andMe Win Your Genome Contest Official Rules

NO ENTRY FEE. NO PURCHASE OR OBLIGATION NECESSARY TO PLAY OR WIN. VOID WHERE PROHIBITED.

1. Eligibility: The 23andMe Win Your Genome Contest (the “Contest”) is open to legal residents of the U.S., age 18 or older, who have an active e-mail account and Internet access as of the beginning of the Contest period. Employees of 23andMe and its affiliates, subsidiaries, advertising and fulfillment agencies, their immediate family members and persons living in their same household, are not eligible to participate in the Contest. Participation in the Contest constitutes entrant’s full and unconditional agreement to and acceptance of these Official Rules (“Official Rules”).

2. To Enter: 23andMe will announce each new Contest on its website at www.spittoon.23andme.com, including the beginning and end dates and times for entries (the “Contest Period”). To enter a Contest, email your entry to contest@23andme.com. One entry per person. All entries must be received by 23andMe during the Contest Period to be eligible.

3. Selection of Winners: Entries will be judged based on the criteria described in the applicable Contest announcement, by a panel of 23andMe employees appropriate for the particular Contest. The decisions of the judges will be final. In the case of any ties, winners will be selected at random from correct entries. Winners will be notified by e-mail.

4. Prizes: Eligible winners will receive the Personal Genome Service (“PGS”) for one person of his or her choice (approximate retail value $999). One prize will be awarded in each Contest. Each PGS shall be subject to 23andMe terms and conditions. Winners are solely responsible for any and all federal, state, and local taxes that apply to prizes, and must provide appropriate taxpayer identification information to 23andMe for reporting purposes. No cash or other substitution of prizes is permitted, except at the sole option of 23andMe for a prize of equal or greater value. 23andMe will not replace any lost or stolen prizes. Odds of winning depend on the number of eligible entries.

5. Notification of Winners: Winners will be notified by e-mail within five (5) business days of selection, and may be required to sign and return an affidavit of eligibility and publicity/liability release within fourteen (14) days of notification. If a selected Winner cannot be contacted, is ineligible, fails to claim a prize and/or where applicable an affidavit of eligibility and publicity/liability release is not timely received, is incomplete or modified, the prize may be forfeited and an alternate Winner will be selected from remaining valid, eligible entries timely submitted. In the event of a dispute regarding who submitted an entry, the entry will be deemed submitted by the authorized account holder of the e-mail account specified in the entry. “Authorized account holder” is defined as the natural person who is assigned to an e-mail address by an Internet access provider, online service provider, or other organization (e.g., business, educational institution, etc.) that is responsible for assigning e-mail addresses for the domain associated with the submitted e-mail address. No automatically generated entries will be accepted.

6. General Rules: By entering, you agree to be bound by these Official Rules. The Contest is offered by 23andMe, Inc., 2606 Bayshore Parkway, Mountain View, CA 94043, which is not responsible for late, lost, delayed, damaged, postage-due, incomplete, illegible, or misdirected entries, responses, or other correspondence, whether by e-mail or postal mail or otherwise, or for theft or destruction or unauthorized access or alterations of entry materials, phone, electrical, network, computer, hardware, software program or transmission malfunctions, failures or difficulties. By participating and winning a prize, Winner releases 23andMe, its affiliates, subsidiaries, directors, officers, employees, and agents, from any and all liability with respect to the Contest or the acceptance, possession or use of any prize, including without limitation (i) any condition caused by events beyond 23andMe’s control that may cause the Contest to be disrupted or corrupted; (ii) any injuries, losses, or damages (compensatory, direct, incidental, consequential or otherwise) of any kind arising in connection with or as a result of the prize, or acceptance, possession, or use of the prize, or from participation in the Contest; and (iii) any printing or typographical errors in any materials associated with the Contest. 23andMe’s decisions in all respects relative to the Contest are final. 23andMe reserves the right, in its sole discretion, to cancel, modify or suspend the Contest in whole or in part, in the event of fraud, technical or other difficulties or if the integrity of the Contest is compromised, without liability to the entrant. 23andMe reserves the right to disqualify any winner, as determined by 23andMe in its sole discretion. All federal, state, and local regulations apply.

7. Additional Conditions: Except where prohibited, by accepting any prize, Winner consents to the use of his/her name, photo and/or likeness, biographical information, winning entry and statements attributed to winner (if true) for advertising and promotional purposes without additional compensation. All entries become property of 23andMe and none will be acknowledged or returned. Allow two (2) weeks for delivery of the Spit Kit, the first step in obtaining the PGS.

8. Winner’s List, Official Rules: For a list of prize winners or a copy of these Official Rules, send your request and a stamped, self-addressed envelope to The 23andMe Win Your Genome Contest, 23andMe, Inc., 2606 Bayshore Parkway, Mountain View, CA 94043 or (for Winner’s list only) send an email message to contest@23andme.com with “Winner’s list” as the email subject and the applicable month Contest in the body of the e-mail.

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I last saw fireworks at a genomics conference in 2000. Back then, euphoria around the first human reference sequence reached a frenzy and many companies including Celera were moving to turn it to commercial advantage, funding a lot of fireworks and champagne in the process. But since then, though the human genome sequence has revolutionized drug development and our understanding of human biology, the average consumer has seen little direct benefit.

Eight years later, this is the second wave. The fireworks are back because a generation of new technologies is promising to drop the cost of generating the complete DNA sequence of any human to $1,000 – though we’re not there yet.

As little as two years ago it still cost $10 million to sequence a human genome. By last year, the price was down to maybe $3 million. At last week’s meeting, that figure dropped precipitously. First there was the unveiling of a human genetic sequence produced for $100,000, using a machine that you can buy today. Then, the same day, there was the announcement that a new machine will soon be available to do the job for an estimated $72,000. By some estimates, the cost of sequencing a human genome could be a few thousand dollars by 2014.

23andMe is already riding this wave. A dozen years ago it would have cost about $600,000 to examine the 580,000 points, known as SNPs, that we include in our $999 service. Eventually we’ll be able to give you your complete sequence for that price.

Genomicists hard at work lowering the cost of genome sequencing.

But at 23andMe we believe, as one of the conference speakers noted, that the bigger challenge right now is collecting so-called phenotypic information. Phenotype is all the physical and behavioral stuff your genotype can affect, such as height, eye color and disease susceptibility. Both genotype and environment influence phenotype, and the research challenge is to gather and interpret the connection between the two. We can then make more detailed and accurate predictions from your genome.

As the smoke blew across the beach, the future seemed clear. Genomic information is already being used for diagnosing novel fatal viruses in transplant recipients, understanding adverse drug responses and determining which mutations a cancer harbors and which drugs may work against it. Prices have come down 100-fold for DNA sequencing in the last five years and will likely continue on that trajectory. In the last talk of the meeting, we learned about a new method of DNA sequencing that might one day enable your genome to be read completely in a few hours. That seems worthy of fireworks.

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Following on the heels of last month’s New England Journal of Medicine study on genetic associations with prostate cancer risk are three new papers in Nature Genetics. The new batch not only replicates earlier discoveries but adds at least 16 potential new associations to the mix. While there are too many to list here individually, a few are worthy of particular mention. (Links to 23andMe’s Genome Explorer (now called Browse Raw Data) are provided for each.)

Iceland’s deCODE Genetics compared the genotypes of 10,000 men diagnosed with prostate cancer with those of 29,000 healthy controls. Instead of conducting a genome-wide association study (GWAS) of hundreds of thousands of single nucleotide polymorphisms (SNPs), the authors chose to follow up on two promising candidates identified in previous GWAS. In the current study, both showed associations to prostate cancer risk.

One of the candidates, rs5945572, is located on the X chromosome. Men only have one X chromosome and thus one copy of rs5945572. Those who had the “A” version of the SNP had slightly higher odds of prostate cancer.

The fact that the SNP is located on the X chromosome—which sons inherit only from their mothers—may help to explain why brothers of men with prostate cancer are at greater risk of being affected than fathers are. If a father has the protective “G” version of the SNP on his X chromosome, he cannot pass it on to his sons; the contribution of this SNP to a man’s risk of prostate cancer is determined by which version his mother passes to him.

The second SNP identified in the deCODE study was rs721048, on chromosome 2. This SNP was analagous to rs2710646, which is in 23andMe’s Genome Explorer (Browse Raw Data). Each copy of the “A” version of rs2710646 slightly raised men’s odds of prostate cancer.

The other two studies each examined 5,000 cases and 5,000 controls. While the studies found a number of significant associations, both independently identified a link between rs10993994 and prostate cancer risk. Each copy of the “T” version of rs10993994 raised men’s odds of prostate cancer. This SNP is located in a gene called MSMB, which encodes a prostate-specific protein thought to be a biomarker for advanced forms of prostate cancer. The authors speculate that the different versions of this SNP might affect levels of the MSMB protein, but this will have to be shown in future experiments.

Further replication studies will have to be performed before all of these associations are fully accepted by the scientific community. But because rs10993994 has already been identified in two large studies, we’ll get it into the Gene Journal article (now called Health and Traits) on prostate cancer as soon as possible. Check back soon to see how this SNP fits into the picture!

(2/12/08 update: added PubMed links to study abstracts. -Andro Hsu)

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23andMe was founded in part to harness the natural curiosity that results when people can see how new knowledge applies to them personally. When new customers join 23andMe they are not just getting access to their genomes and the scientific knowledge that gives it meaning – they are also contributing their genetic information to our research database. The hope of 23andMe is that they will be willing to take the next step and contribute additional information to enable the creation of even more knowledge.

As the Nature Genetics editors observed, “it would be wrong to underestimate the motivational potential inherent in handing people their genomes and asking them to participate in finding out more … ”

Once our database is large enough, we plan to ask our customers to provide additional information beyond their genetic data – it could be anything from symptoms of autism to shoe size. That information would be used in research that could discover even more genetic links to traits and diseases.

Participation in these follow-on studies will be voluntary, but we believe that our customers’ curiosity and generosity will motivate them to take part. Our customers may even want to propose and help organize their own studies.

The beauty of this arrangement is that every discovery our customers contribute to has the potential to make their own data that much more meaningful and valuable, and we think it could lead to rapid advancement in understanding of the human genome in general. We envision a virtuous circle of inquiry and discovery, as our customers repeatedly lend their data for research and reap the benefits of the new knowledge it produces, whether directly or indirectly.

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