The Daya Bay experiment has observed correlations between reactor core fuel evolution and changes in the reactor antineutrino flux and energy spectrum. Four antineutrino detectors in two experimental halls were used to identify 2.2 million inverse beta decays (IBDs) over 1230 days spanning multiple fuel cycles for each of six 2.9 G Wth reactor cores at the Daya Bay and Ling Ao nuclear power plants. Using detector data spanning effective 239Pu fission fractions F239 from 0.25 to 0.35, Daya Bay measures an average IBD yield σ̄f of (5.90 ±0.13 )×10-43 cm2/fission and a fuel-dependent variation in the IBD yield, d σf/d F239, of (-1.86 ±0.18 )×10-43 cm2/fission . This observation rejects the hypothesis of a constant antineutrino flux as a function of the 239Pu fission fraction at 10 standard deviations. The variation in IBD yield is found to be energy dependent, rejecting the hypothesis of a constant antineutrino energy spectrum at 5.1 standard deviations. While measurements of the evolution in the IBD spectrum show general agreement with predictions from recent reactor models, the measured evolution in total IBD yield disagrees with recent predictions at 3.1 σ . This discrepancy indicates that an overall deficit in the measured flux with respect to predictions does not result from equal fractional deficits from the primary fission isotopes 235U, 239Pu, 238U, and 241Pu. Based on measured IBD yield variations, yields of (6.17 ±0.17 ) and (4.27 ±0.26 )×10-43 cm2 /fission have been determined for the two dominant fission parent isotopes 235U and 239Pu. A 7.8% discrepancy between the observed and predicted 235U yields suggests that this isotope may be the primary contributor to the reactor antineutrino anomaly.