Understanding Molecular Clocks and Time Trees

2021 ◽  
pp. 326-337
Author(s):  
Andrew V. Z. Brower ◽  
Randall T. Schuh
Keyword(s):  
Amino Acid ◽  
Molecular Clock ◽  
Significant Error ◽  
Evolutionary Tree ◽  
Molecular Clocks ◽  
Amino Acid Substitutions ◽  
Absolute Minimum ◽  
Short Time ◽  
Over Time ◽  
Age Estimates

This chapter examines molecular clocks and time trees. Although laden with numerous process assumptions that may or may not be true (or knowable), the idea is appealingly straightforward: if amino acid substitutions in proteins occurred at a relatively steady pace that were more or less constant both over time and along each of the branches of a diverging evolutionary tree, then the number of substitutions would be directly related to the time since the taxa in question diverged from one another. However, evidence does not support a universal molecular clock. Evidence might or might not support “local” clocklike evolution among closely related taxa over relatively short time spans. Although absolute minimum ages for clades may be inferred from fossils, from biogeographical patterns, or extrapolated from secondary calibrations, such age estimates are subject to potentially significant error due to vagaries of geological dating as well as ambiguities of fossil identity. The test of a time tree hypothesis is to discover new fossil evidence that corroborates or falsifies it.

scholarly journals Tips and nodes are complementary not competing approaches to the calibration of molecular clocks

2016 ◽  
Vol 12 (4) ◽  
pp. 20150975 ◽  
Author(s):  
Joseph E. O'Reilly ◽  
Philip C. J. Donoghue
Keyword(s):  
Molecular Clock ◽  
Divergence Time ◽  
Molecular Clocks ◽  
Fossil Species ◽  
Divergence Time Estimates ◽  
Time Estimates ◽  
Fossil Evidence ◽  
Accuracy And Precision ◽  
Age Constraints ◽  
Age Estimates

Molecular clock methodology provides the best means of establishing evolutionary timescales, the accuracy and precision of which remain reliant on calibration, traditionally based on fossil constraints on clade (node) ages. Tip calibration has been developed to obviate undesirable aspects of node calibration, including the need for maximum age constraints that are invariably very difficult to justify. Instead, tip calibration incorporates fossil species as dated tips alongside living relatives, potentially improving the accuracy and precision of divergence time estimates. We demonstrate that tip calibration yields node calibrations that violate fossil evidence, contributing to unjustifiably young and ancient age estimates, less precise and (presumably) accurate than conventional node calibration. However, we go on to show that node and tip calibrations are complementary, producing meaningful age estimates, with node minima enforcing realistic ages and fossil tips interacting with node calibrations to objectively define maximum age constraints on clade ages. Together, tip and node calibrations may yield evolutionary timescales that are better justified, more precise and accurate than either calibration strategy can achieve alone.

Recombinant Variants of Tissue-Type Plasminogen Activator Containing Amino Acid Substitutions in the Finger Domain

1992 ◽  
Vol 68 (06) ◽  
pp. 672-677 ◽  
Author(s):  
Hitoshi Yahara ◽  
Keiji Matsumoto ◽  
Hiroyuki Maruyama ◽  
Tetsuya Nagaoka ◽  
Yasuhiro Ikenaka ◽  
...  
Keyword(s):  
Amino Acid ◽  
Plasminogen Activator ◽  
Half Life ◽  
Tissue Type ◽  
Clot Lysis ◽  
Amino Acid Substitutions ◽  
Wild Type ◽  
Plasma Clot ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

SummaryTissue-type plasminogen activator (t-PA) is a fibrin-specific agent which has been used to treat acute myocardial infarction. In an attempt to clarify the determinants for its rapid clearance in vivo and high affinity for fibrin clots, we produced five variants containing amino acid substitutions in the finger domain, at amino acid residues 7–9, 10–14, 15–19, 28–33, and 37–42. All the variants had a prolonged half-life and a decreased affinity for fibrin of various degrees. The 37–42 variant demonstrated about a 6-fold longer half-life with a lower affinity for fibrin. Human plasma clot lysis assay estimated the fibrinolytic activity of the 37–42 variant to be 1.4-fold less effective than that of the wild-type rt-PA. In a rabbit jugular vein clot lysis model, doses of 1.0 and 0.15 mg/kg were required for about 70% lysis in the wild-type and 37–42 variant, respectively. Fibrinogen was degraded only when the wild-type rt-PA was administered at a dose of 1.0 mg/kg. These findings suggest that the 37–42 variant can be employed at a lower dosage and that it is a more fibrin-specific thrombolytic agent than the wild-type rt-PA.

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