More Neanderthal Data

One of the better sources for up-to-date information regarding Neanderthal admixture has been John Hawks' weblog. Hawks is a paleoanthropologist at the University of Wisconsin, and in addition to providing links to and commentary upon some of the latest research, Hawks and his students have been working at replicating and extending some of the more interesting findings regarding the Neanderthal genome and its presence in modern humans.

An excellent overview of the process is contained in this post from last week, and in it you will find a thorough but easily accessible explanation for how scientists arrive at the 1-4% admixture estimate of Neanderthal genetic material into non-African humans. In the original paper describing Neanderthal admixture (Green 2010), only five modern human genomes—two African and three non-African—were compared to the Neanderthal draft sequence. Hawks and his students have been making much the same comparison against a much larger database of modern genomes, with some clarifying results. Their work is of course still preliminary and not reviewed (and thus should be taken with a grain of salt), but if it proves to be accurate, it leads to some interesting conclusions:

• The admixture finding from (Green 2010) is being convincingly replicated and confirmed as the genomes from more and more present-day humans are being compared to the draft sequence of the Neanderthal genome. Either the draft sequence has some very bad data, or the assumptions behind the genome comparison techniques are totally without merit, or Neanderthal admixture into non-African humans is a confirmed reality—there doesn't seem to be any other way around it.
• The mean amount of Neanderthal admixture into non-African populations (over and above any admixture into African populations) looks to be around 3%.
• Although 3% is the mean, the variability remains significantly wide: any given non-African individual might easily fall within the range of 2-4% admixture, and there are indications some individuals will fall well outside that range. Even within families, there might be significant variability.
• All indications are that the Neanderthal admixture is shuffled throughout much of the modern human genome. That is, person A might have 3% admixture and person B might have 3% admixture, but the two may share relatively little admixture in common. It's not specific parts of the modern genome that are Neanderthal derived; instead, it appears that much of the modern non-African genome has been impacted in a shuffled-up sort of way.
• The mean Neanderthal admixture difference between Europeans and Asians is extremely small. This result goes against the idea that an out-of-Africa migrating population interbred primarily with Western European Neanderthals around 35 to 40 thousand years ago. Instead, this result points more plausibly to the idea that admixture happened earlier in time and/or at another locale (such as the Middle East).
• All these findings are based solely upon SNP analysis. The other sources of genetic differentiation—such as duplication, deletion, insertion, inversion—still await less costly and more accurate analysis. But in these areas too, Neanderthal admixture might be expected to have significant impact.

None of these findings provide any direct evidence for my idea that autism is a species-differentiation event (in particular, a species dis-recognition event), but neither do any of these findings contradict the idea. As I've said elsewhere, what we can look for now are studies comparing the Neanderthal draft sequence to modern humans diagnosed with such things as autism, schizophrenia and bipolar. If my idea is going to have any legs, then what we might expect to find are Neanderthal-distinguishing genetic signatures among these diagnosed populations, either admixture amounts outside the norm (most likely higher than the typical range) or a specific pattern of relationship against the Neanderthal genome unique to the diagnosed population. Given the rapid rate of technology advancement in this area, we might not have to wait all that much longer.

One other thing: as I read through these Neanderthal admixture findings, I can't help but be reminded of the genetic research conducted so far in the areas of autism, schizophrenia and bipolar. In each instance, researchers have been uncovering extremely lengthy lists of candidate genetic markers for the condition, markers that show up in only a tiny percentage of the affected population and markers that are scattered almost at random throughout the genome. This of course also does not provide any direct evidence that Neanderthal admixture is playing a role in such conditions, but the genetic similarities are difficult not to notice. And contrast this with the dubious conclusion being drawn by the autism research community, a community that insists on casting all these genetic variations as genetic defects, each leading (by miraculous coincidence, it would seem) to the same neurological and phenotypic outcome. There is a difference between the words “speculative” and “implausible,” and I see that difference on display here.

(Green 2010): Green, Richard E. and others. 2010. “A Draft Sequence of the Neandertal Genome.” Science 328:710–22

Ami Klin's Good Science

Can someone explain to me how Ami Klin's research team in (Shultz 2011) could have possibly overlooked the idea of running a second version of their experiment, one employing a visual scene more naturally appealing to autistic perception? It would have been so easy: remove the humans from the scene and through automated means have the toy wagon's door open and shut on a regular basis. Bring in another group of controls and autistic children, and make the same measurements as were made for the first scenario. The comparisons across populations and across scenarios might have provided a wealth of information for both autistic and non-autistic perception, probably far more than was provided by the study as conducted.

Any decent research team might have recognized the potential in that second scenario, but it was criminally stupid for the Klin research team not to have recognized it, because the team had already been through that experience!

The whole beauty of (Klin 2009) was that instead of the nothing-new experiment the authors had originally designed, and prompted by the “serendipitous” observations of a fifteen-month-old autistic girl, the study team was able to re-configure the experiment to test for both non-autistic appealing and autistic appealing scenarios, thereby setting up a wealth of cross-population, cross-scenario information for comparison and contrast. That serendipitous enhancement literally made the study.

So you would think the Klin team would know by now the value of taking that broader approach with every experiment going forward. You would think. But apparently the fifteen-month-old autistic girl didn't hit them upside the head hard enough.

I can't describe how dumbfounded I am by the scientific blindness I see on display almost everywhere in the autism research community. People go on and on to me about the need to weed out bad science and to expose all the charlatans and to have better standards, and on and on and on they go. For what, I ask? For this? For more of Ami Klin's inability to see beyond the end of his own nose? Is this the good science everyone's striving for? Hell, I'd rather have the charlatans. At least the charlatans know what they're doing.

(Shultz 2011): Shultz, Sarah; Klin, Ami; Jones, Warren. 2011. “Inhibition of eye blinking reveals subjective perceptions of stimulus salience.” PNAS (in press).

(Klin 2009): Klin, Ami; Lin, David J.; Gorrindo, Phillip; Ramsay, Gordon; Jones, Warren. 2009. “Two-year-olds with Autism Orient to Non-Social Contingencies Rather than Biological Motion.” Nature 459: 257–61.

Competing Speculative Hypotheses

About a year ago, I wrote a rather lengthy essay (Griswold 2011) inspired by the paleoanthropologist Richard Klein and his ideas regarding the behavioral and cultural changes known as the human great leap forward. Here (http://www.youtube.com/watch?v=qUp_6n8x3D0) you can watch a recent 45-minute lecture by Dr. Klein on the topic, and although I think his written works (for instance, (Klein 2002) and (Klein 2008)) provide better detail, the video lecture does give a reasonable introduction and overview to Klein's approach and is well worth the short investment of time.

Near the very end of the lecture, after having outlined arguments and evidence for the notion that the human great leap forward was a sudden event—occurring around fifty thousand years ago—Klein states his hypothesis that the sudden event must have been launched by a genetic mutation, one producing significant cognitive effect. Klein then briefly mentions the recent and preliminary work on the mapping of the Neanderthal genome (Green 2010), work that has led to two major (and still preliminary) results: 1. there is now a list (a fairly short list) of modern human/non-Neanderthal gene sequences that would serve as obvious candidates for recent genetic mutation; and 2. nearly all non-African modern humans carry a small influence (estimated in the neighborhood of 2.5%) of Neanderthal-originated genetic material.

As Klein mentions in his lecture, the first result opens the door to a means for testing his genetic mutation hypothesis. The idea would be to obtain a list of modern human genetic sequences that differ significantly from those of ancient humans (including Neanderthals) and see if a subset of these produce the kind of neurological impact consistent with human behavioral and cognitive change. There are of course some technical challenges that stand in the way of this approach: for one, the genome mappings are still in need of greater clarification and accuracy, and furthermore, scientists have not yet been all that successful in connecting genetic material to phenotypic effect, be it cognitive or otherwise. Nonetheless, these are challenges that might be expected to be overcome through technological advances, and so indeed, Klein's hypothesis might one day soon be put to a thorough scientific test.

As I outlined in (Griswold 2011), I'm fairly convinced Klein is going to be disappointed in the results of that test. Although I concur with Klein's assertion that the human great leap forward was a sudden anthropological event, I see an incongruity undermining Klein's explanation for that event. Although most scientists, Klein included, would take for granted that human cognitive advancement must have been driven by a genetic/neurological/evolutionary change, nearly everything scientists can actually demonstrate about genetics, neurology and evolution runs counter to the type of sudden, population-wide, large-scale event Klein is describing. It's as though the animal world had gone sightless for billions of years and then overnight one of the species popped up a pair of excellent eyes and immediately conquered the rest of the planet through this new-found vision. It makes for a dramatic story, but biology doesn't seem to work that way.

Genetically-driven evolutionary change does of course happen, but not on the time or impact scale Klein is proposing (and not even on the time or impact scale that cultural evolutionists would propose). On the one hand, Klein's description of sudden human behavioral and cognitive change looks accurate enough based upon the archaeological evidence, but on the other hand, his explanation for that sudden change looks utterly implausible based upon the logic of biology.

That said, it would still be prudent to wait for the science.

Also in the video lecture, almost as an aside, Klein dismisses the other major finding from Neanderthal genome mapping—the admixture of Neanderthal genetic material into modern humans—suggesting that as details of the respective genomes become more complete and accurate, this finding will prove to be false. Logically speaking, however, Klein doesn't need to make that dismissal: it's perfectly possible that Neanderthal admixture will continue to hold upon further analysis, and yet its impact on human behavioral and cognitive change will prove nonetheless to be benign. I think what's driving Klein's desire to dismiss the admixture finding is that he wants to emphasize how modern Homo sapiens—post genetic mutation—were so cognitively and behaviorally advanced over their Neanderthal contemporaries that all they could do was swamp the Neanderthals into extinction, not interact with or incorporate them. That's a reasonable conclusion to draw given what we already know about European replacement of Neanderthals (evidence for which Klein has intimate working knowledge), but in point of fact there's nothing about the Neanderthal admixture finding that implies it had to be a post out-of-Africa event—the evidence for the timing of that admixture remains inconclusive, and it's quite possible any such admixture could have taken place near the beginning or even prior to the out-of-Africa migration.

Here too, it would be prudent to wait for the science.

My own interest in the Neanderthal admixture finding is that it serves as possible evidence for an alternative explanation to the human great leap forward, an explanation I find logically more plausible—albeit perhaps just as speculative—as Richard Klein's. In (Griswold 2011) I outline how the introduction of autism into the human population—autistic perception in particular—could have served as the catalyst driving human cognitive and behavioral change. I won't repeat the details here, but the concepts at work are a description of autism as a lack of species recognition; autistic perception as a compensatory foregrounding of non-biological pattern, structure, symmetry and form; human cognitive and behavioral advancement as the environmental accumulation of these very same elements of non-biological pattern, structure, symmetry and form; and Neanderthal admixture as the conceivable biological cause for autism-related species dis-recognition. Under my scenario, all these concepts would have come together in a kind of circumstantial stew that began cooking around fifty thousand years ago.

With the ongoing advancements in human genome sequencing, parts of my autism hypothesis might become just as amenable to scientific testing as Klein's genetic mutation hypothesis. The key evidence to look for is whether large or distinctive presences of Neanderthal-derived genetic material within individuals correlates significantly to diagnoses of autism (and perhaps to similar conditions of schizophrenia and bipolar). A high and distinctive correlation would be supportive for describing autism as a condition of species dis-recognition, and thereby indirectly supportive of an autism-related explanation for mankind's great leap forward.

Of course it's also possible that neither speculation—mine nor Richard Klein's—will prove to be helpful, and it will be some other explanation, perhaps one not yet thought of, that manages to untangle the mysteries from fifty thousand years ago. But one thing is for certain: these recent advancements in human genome mapping are opening an intriguing window onto our anthropological past. It's an excellent time to be alive if one is prone to asking such questions as, what caused human beings to become so distinctively human?

(Green 2010): Green, Richard E. and others. 2010. “A Draft Sequence of the Neandertal Genome.” Science 328:710–22

(Griswold 2011): Griswold, Alan. 2011. Autistic Songs. Bloomington, IN: iUniverse.

(Klein 2002): Klein, Richard G. 2002. The Dawn of Human Culture. New York: Wiley.

(Klein 2008): Klein, Richard G. 2008. "Out of Africa and the Evolution of Human Behavior." Evolutionary Anthropology 17:267–81.

The Joy of Meta

Here is an abstract from the very latest in autism research:

Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures (‘four major areas’). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics (‘four comparison areas’). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006–2010). Evaluation of trends between the four major areas and the four comparison areas demonstrated that the largest relative growth was in immune dysregulation/inflammation, oxidative stress, toxicant exposures, genetics and neuroimaging. Research on mitochondrial dysfunction started growing in the last 5 years. Theory of mind and neuropathology research has declined in recent years. Although most publications implicated an association between the four major areas and ASD, publication bias may have led to an overestimation of this association. Further research into these physiological areas may provide insight into general or subset-specific processes that could contribute to the development of ASD and other psychiatric disorders.

I'm not sure how badly you'll want to delve into all that verbiage, but in short it's an assessment of various "abnormalities" associated with autism through the means of looking at research publication trends. For instance, the association of mitochondrial dysfunction with autism is assessed by looking at the rising number of mitochondria-autism research articles published over the calendar years from 1971 to 2010. It's the type of work that can be done with a good search engine and a spreadsheet program (3D color graphics would be a bonus).

In other words, it's a shitty piece of meta-analysis.

Of course, there have been better examples of meta-analysis applied to autism research, but this raises an intriguing question. How does one differentiate good meta-analysis from bad meta-analysis (think of how important this will be to Ben Goldacre as he's writing his next book, Bad Meta Science)? Well obviously, what we need to do is institute some standards, protocols and ethics for the general practice of meta-analysis, and once these are in place we can begin performing meta-analyses of all the meta-analyses. And if there happen to be any lingering problems, we can just ask Janet Stemwedel to remind the tribe of meta scientists of all their meta social duties.

No really. I think this would be a fruitful line of endeavor. As far as I can tell, the possibilities for employment are unlimited.

Autism Etiology

Genetics, neurology, environment—permutations and combinations aplenty, plausible mechanisms afew.

Dispelling the Fog

Why try to deny the Flynn effect or pass it off as a short-term anomaly? If we embrace the Flynn effect for exactly what it says, the faulty explanations disappear.