This means that the observed number of changes is no longer linear with time, but instead flattens out.
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The notion of the existence of a so-called "molecular clock" was first attributed to Emile Zuckerkandl and Linus Pauling who, in 1962, noticed that the number of amino acid differences in hemoglobin between different lineages changes roughly linearly with time, as estimated from fossil evidence.
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The lack of a distinct toothcomb in the fossil record prior to 40 mya has created a conflict with molecular clock studies that suggest an older divergence between lemurs and lorisoids, and the existence of a ghost lineage of lemuriform primates in Africa.
Heterodimer CLOCK-BMAL1 activates E-box elements present in the Per1 promoter, as well activating the E box promoters of other components of the molecular clock such as PER2, CRY1, and CRY2.